METTL21A

Chr 2

methyltransferase 21A, HSPA lysine

Also known as: FAM119A, HCA557b, HSPA-KMT

NCBI Gene: 151194 ENSG00000144401 UniProt: Q8WXB1 OMIM: 615257

This protein-lysine methyltransferase selectively trimethylates specific lysine residues in heat shock protein 70 (HSP70) family members, including HSPA1 and HSPA8. The gene is not highly constrained against loss-of-function variants, and currently no definitive human disease associations have been established for METTL21A mutations in the provided clinical data.

OMIM ResearchSummary from RefSeq, UniProt

Enables ATPase binding activity; Hsp70 protein binding activity; and protein-lysine N-methyltransferase activity. Involved in peptidyl-lysine methylation. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2025]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.36

Clinical Summary— METTL21A

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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

26 VUS of 34 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?

1.36LOEUF

pLI 0.001

Z-score 0.83

OE 0.69 (0.38–1.36)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.04Z-score

OE missense 1.01 (0.87–1.17)

123 obs / 121.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.69 (0.38–1.36)

0≤0.351.4

Missense OE?1.01 (0.87–1.17)

0≤0.61.4

Synonymous OE?0.85

0≤1.21.6

LoF obs/exp: 6 / 8.6Missense obs/exp: 123 / 121.7Syn Z: 0.81

This gene — mechanism propensity

0.7035th %ile

GOF

0.5955th %ile

LOF

0.2092th %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

34 submitted variants in ClinVar

ClinVar

Classification Summary

VUS26

Benign1

VUS

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	26	0	26
Likely Benign	0	0	0
Benign	0	1	1
Total	26	1	27

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

View in ClinVar →

26 pathogenic / likely-pathogenic (of 27) ClinVar copy-number / structural variants overlap METTL21A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →