CSN1S1

Chr 4

casein alpha s1

Also known as: CASA, CSN1

NCBI Gene: 1446 ENSG00000126545 UniProt: P47710 OMIM: 115450

The protein is a major milk protein with an important role in the capacity of milk to transport calcium phosphate. Mutations cause autosomal recessive congenital lactase deficiency, which presents in infancy with severe diarrhea, dehydration, and failure to thrive when exposed to lactose-containing milk. The gene shows very low constraint to loss-of-function variants, consistent with its specialized role in milk composition rather than essential cellular functions.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to be involved in several processes, including response to 11-deoxycorticosterone; response to dehydroepiandrosterone; and response to progesterone. Located in extracellular space. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.71

Clinical Summary— CSN1S1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

16 VUS of 20 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.71LOEUF

pLI 0.000

Z-score -0.85

OE 1.22 (0.87–1.71)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.32Z-score

OE missense 0.90 (0.75–1.09)

80 obs / 88.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.22 (0.87–1.71)

0≤0.351.4

Missense OE?0.90 (0.75–1.09)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 22 / 18.1Missense obs/exp: 80 / 88.5Syn Z: 0.14

This gene — mechanism propensity

0.79top 25%

GOF

0.5954th %ile

LOF

0.1598th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

20 submitted variants in ClinVar

ClinVar

Classification Summary

VUS16

Likely Benign2

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	16	0	16
Likely Benign	1	1	2
Benign	0	1	1
Total	17	2	19

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

22 pathogenic / likely-pathogenic (of 33) ClinVar copy-number / structural variants overlap CSN1S1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →