Is HAP1 p.Thr441Met (c.1322C>T) pathogenic?

HAP1 p.Thr441Met (c.1322C>T) is classified Benign in HAP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-06-11). AlphaMissense: likely benign (0.098); Common (popmax 34.1%, sas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about HAP1 p.Thr441Met (c.1322C>T)?

AlphaMissense predicts likely benign (score 0.098) — an in-silico prediction, not a clinical call.

HAP1 p.Thr441Met

Q: How common is HAP1 p.Thr441Met (c.1322C>T) in the general population?

HAP1 p.Thr441Met (c.1322C>T) is common (popmax 34.1%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1322C>T · rs4523977 · VCV1242257

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.098 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 34.1%, sas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.098	likely benign
REVEL	0.012	strongly benign-leaning
SaProt	LLR -7.97	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.2	GERP -1.8
Regional constraint	o/e 1.05	unconstrained · MANE · 9,930 bp · p 0.16 · regional, not allelic
Overall
CADD	0.284	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM T493M vs ClinVar T441M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 34.1% South Asian · 30,356/89,146 alleles

Filtering AF 33.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 33.6%

Overall 22.7% 359,727/1,584,764 alleles · common exomes 332,256/1,432,670 · genomes 27,471/152,094 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	34.1%	3
Finnishnot grpmax-eligible	26.8%	4
East Asian	25.6%	4
Ashkenazi Jewishnot grpmax-eligible	25.2%	4
European (non-Finnish)	22.7%	4
Admixed American	22.5%	4
Remaining individualsnot grpmax-eligible	22.2%	5
Middle Eastern	22%	5
Amishnot grpmax-eligible	21.9%	5
African / African-American	3.82%	26

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: HAP1
Protein: p.Thr441Met
Coding: c.1322C>T
MANE Select: NM_177977
dbSNP: rs4523977
Type: single nucleotide variant
Location: chr17:41727098 (GRCh38)
Gene constraint: LOEUF 1.31 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.28
Residue 493 UniProt numbering: a UniProt-annotated variant site (may influence the age-at-onset of huntington disease; increases binding to mutated htt; influences htt degradation)

Full HAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HAP1 p.Thr441= Likely benign same residue
HAP1 p.Arg106Pro Uncertain significance ★★ ⚠ same type
HAP1 p.Cys25Tyr Benign ★★ same type
HAP1 p.Gly604Arg Benign ★★ same type
HAP1 p.Ile496Val Benign ★★ same type
HAP1 p.Leu348= Benign ★★ same type
HAP1 p.Ser616Ter Benign ★★ same type
HAP1 p.Thr66Ala Likely benign ★★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/hap1-p-thr441met (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown