Is HAP1 p.Thr66Ala (c.196A>G) pathogenic?

HAP1 p.Thr66Ala (c.196A>G) is classified Likely benign in HAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-07). AlphaMissense: likely benign (0.0782); Rare (popmax 0.839%, afr).

How common is HAP1 p.Thr66Ala (c.196A>G) in the general population?

HAP1 p.Thr66Ala (c.196A>G) is rare (popmax 0.839%, afr) (gnomAD).

What do computational predictors say about HAP1 p.Thr66Ala (c.196A>G)?

AlphaMissense predicts likely benign (score 0.0782) — an in-silico prediction, not a clinical call.

HAP1 p.Thr66Ala

c.196A>G · rs77781133 · VCV730350

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0782 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.839%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0782	likely benign
REVEL	0.011	strongly benign-leaning
SaProt	LLR -4.77	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.71	GERP -2.4, phastCons 0.001
Regional constraint	o/e 1.05	unconstrained · MANE · 9,930 bp · p 0.16 · regional, not allelic
Overall
CADD	2.137	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.839% African / African-American · 629/74,942 alleles

Filtering AF 0.785% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.763%

Overall 0.0458% 737/1,608,578 alleles · rare exomes 351/1,456,300 · genomes 386/152,278 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.839%	119
Admixed American	0.0935%	1,070
Remaining individualsnot grpmax-eligible	0.0643%	1,556
Middle Eastern	0.0166%	6,040
European (non-Finnish)	0.000935%	106,966

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.Thr66Ala
Coding: c.196A>G
MANE Select: NM_177977
dbSNP: rs77781133
Type: single nucleotide variant
Location: chr17:41734439 (GRCh38)
Gene constraint: LOEUF 1.31 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.28
Residue 66: the 'disordered' region

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

Similar variants

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.Thr441Met Benign ★★ same type
HAP1 p.Val369Ala 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-thr66ala (accessed [today's date]).

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