Is CHAC2 p.Ile127Thr (c.380T>C) pathogenic?

CHAC2 p.Ile127Thr (c.380T>C) is classified Uncertain significance in CHAC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-21). AlphaMissense: ambiguous (0.3452); Very rare (popmax 0.00892%, eas).

How common is CHAC2 p.Ile127Thr (c.380T>C) in the general population?

CHAC2 p.Ile127Thr (c.380T>C) is very rare (popmax 0.00892%, eas) (gnomAD).

What do computational predictors say about CHAC2 p.Ile127Thr (c.380T>C)?

AlphaMissense predicts ambiguous (score 0.3452) — an in-silico prediction, not a clinical call.

CHAC2 p.Ile127Thr

c.380T>C · rs531154748 · VCV2558986

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3452 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00892%, eas)

Computational evidence

Protein change
AlphaMissense	0.3452	ambiguous
REVEL	0.529	indeterminate
SaProt	LLR -11.66	damaging
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.9	GERP 2.9, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 6,635 bp · p 0.0017 · regional, not allelic
Overall
CADD	25.2	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 0.00892% East Asian · 4/44,852 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000558% 9/1,613,212 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00892%	11,213
Remaining individualsnot grpmax-eligible	0.0032%	31,228
Admixed American	0.00167%	59,822
European (non-Finnish)	0.00017%	589,925

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.Ile127Thr
Coding: c.380T>C
MANE Select: NM_016115 · reported on NM_001008708
dbSNP: rs531154748
Type: single nucleotide variant
Location: chr2:53774350 (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-ile127thr (accessed [today's date]).

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