Is CHAC2 p.Glu74Val (c.221A>T) pathogenic?

CHAC2 p.Glu74Val (c.221A>T) is classified Uncertain significance in CHAC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-03). AlphaMissense: likely benign (0.2012); Ultra-rare (popmax 0.0165%, mid).

How common is CHAC2 p.Glu74Val (c.221A>T) in the general population?

CHAC2 p.Glu74Val (c.221A>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CHAC2 p.Glu74Val (c.221A>T)?

AlphaMissense predicts likely benign (score 0.2012) — an in-silico prediction, not a clinical call.

CHAC2 p.Glu74Val

c.221A>T · VCV4001991

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2012 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2012	likely benign
REVEL	0.383	indeterminate
SaProt	LLR -11.47	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 6,635 bp · p 0.0017 · regional, not allelic
Overall
CADD	27.3	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 0.0165% Middle Eastern · 1/6,078 alleles

Filtering AF 0.00752% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00594%

Overall 0.00149% 24/1,613,140 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,078
South Asian	0.0132%	7,572
African / African-American	0.00668%	14,972
Admixed American	0.00167%	59,796
Remaining individualsnot grpmax-eligible	0.0016%	62,428
European (non-Finnish)	0.000339%	294,936

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: CHAC2
Protein: p.Glu74Val
Coding: c.221A>T
MANE Select: NM_016115 · reported on NM_001008708
Type: single nucleotide variant
Location: chr2:53774191 (GRCh38)

Full CHAC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/chac2-p-glu74val (accessed [today's date]).

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