KRTAP10-12

Chr 21

keratin associated protein 10-12

Also known as: KAP10.12, KRTAP18-12, KRTAP18.12

NCBI Gene: 386685 ENSG00000189169 UniProt: P60413

Encodes a keratin-associated protein that forms the interfilamentous matrix in hair cortex by cross-linking with hair keratins through disulfide bonds to create the rigid hair shaft structure. Mutations cause autosomal recessive woolly hair, a structural hair disorder characterized by tightly curled, fine hair texture present from birth. This gene shows low constraint against loss-of-function variants, consistent with its recessive inheritance pattern.

Summary from RefSeq, UniProt

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Active trials

Pubs (1 yr)

P/LP submissions

P/LP missense

1.25

LOEUF

Multiple*

Mechanism· predicted

Clinical Summary— KRTAP10-12

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

89 unique Pathogenic / Likely Pathogenic· 81 VUS of 179 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

1.25LOEUF

pLI 0.010

Z-score 1.14

OE 0.55 (0.27–1.25)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint

-1.28Z-score

OE missense 1.31 (1.16–1.48)

182 obs / 139.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios

LoF OE0.55 (0.27–1.25)

0≤0.351.4

Missense OE1.31 (1.16–1.48)

0≤0.61.4

Synonymous OE1.35

0≤1.21.6

LoF obs/exp: 4 / 7.3Missense obs/exp: 182 / 139.5Syn Z: -2.15

0.93top 5%

GOF

0.85top 5%

LOF

0.2679th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction 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.