Is CHAC2 p.Leu181Phe (c.541C>T) pathogenic?

CHAC2 p.Leu181Phe (c.541C>T) is classified Uncertain significance in CHAC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-06). AlphaMissense: likely benign (0.0733); Ultra-rare (popmax 0.0129%, sas).

How common is CHAC2 p.Leu181Phe (c.541C>T) in the general population?

CHAC2 p.Leu181Phe (c.541C>T) is ultra-rare (popmax 0.0129%, sas) (gnomAD).

What do computational predictors say about CHAC2 p.Leu181Phe (c.541C>T)?

AlphaMissense predicts likely benign (score 0.0733) — an in-silico prediction, not a clinical call.

CHAC2 p.Leu181Phe

c.541C>T · VCV3266768

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0733 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0129%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0733	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -8.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -0.22	GERP -5.8
Regional constraint	o/e 1.21	unconstrained · MANE · 6,635 bp · p 0.0017 · regional, not allelic
Overall
CADD	5.863	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0129% South Asian · 10/77,624 alleles

Filtering AF 0.00689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00523%

Overall 0.00155% 24/1,544,414 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0129%	7,762
Remaining individualsnot grpmax-eligible	0.00504%	19,855
African / African-American	0.00138%	72,240
European (non-Finnish)	0.000869%	115,117

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.Leu181Phe
Coding: c.541C>T
MANE Select: NM_016115 · reported on NM_001008708
Type: single nucleotide variant
Location: chr2:53774511 (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-leu181phe (accessed [today's date]).

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