Is CHAC2 p.Leu108Pro (c.323T>C) pathogenic?

CHAC2 p.Leu108Pro (c.323T>C) is classified Uncertain significance in CHAC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-08). AlphaMissense: likely pathogenic (0.9503); Absent from gnomAD v4.1.

How common is CHAC2 p.Leu108Pro (c.323T>C) in the general population?

CHAC2 p.Leu108Pro (c.323T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CHAC2 p.Leu108Pro (c.323T>C)?

AlphaMissense predicts likely pathogenic (score 0.9503) — an in-silico prediction, not a clinical call.

CHAC2 p.Leu108Pro

c.323T>C · VCV3491816

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9503 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9503	likely pathogenic
REVEL	0.764	pathogenic-leaning
SaProt	LLR -15.34	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 6,635 bp · p 0.0017 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CHAC2
Protein: p.Leu108Pro
Coding: c.323T>C
MANE Select: NM_016115 · reported on NM_001008708
Type: single nucleotide variant
Location: chr2:53774293 (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-leu108pro (accessed [today's date]).

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