Is CHCHD2 p.Ala32Pro (c.94G>C) pathogenic?

CHCHD2 p.Ala32Pro (c.94G>C) is classified Uncertain significance in CHCHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-17). AlphaMissense: likely benign (0.0861); Very rare (popmax 8.49e-05%, nfe).

How common is CHCHD2 p.Ala32Pro (c.94G>C) in the general population?

CHCHD2 p.Ala32Pro (c.94G>C) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about CHCHD2 p.Ala32Pro (c.94G>C)?

AlphaMissense predicts likely benign (score 0.0861) — an in-silico prediction, not a clinical call.

CHCHD2 p.Ala32Pro

c.94G>C · rs145190179 · VCV2192193

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0861 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0861	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -9.82	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 0.56	phastCons 0.79
Regional constraint	o/e 0.88	unconstrained · MANE · 4,559 bp · p 0.078 · regional, not allelic
Overall
CADD	18.25	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 8.49e-05% European (non-Finnish) · 1/1,178,384 alleles

Overall 6.21e-05% 1/1,609,318 alleles · very rare exomes 0/1,457,292 · genomes 1/152,026 · joint denominator

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: CHCHD2
Protein: p.Ala32Pro
Coding: c.94G>C
MANE Select: NM_016139
dbSNP: rs145190179
Type: single nucleotide variant
Location: chr7:56104432 (GRCh38)
Gene constraint: LOEUF 1.586 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.86 · 2 PDB
Residue 32: the 'disordered' region

Full CHCHD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHCHD2 p.Ala32Thr Uncertain significance ★★ ⚠ same residue
CHCHD2 c.446-9T>A Uncertain significance ★★ same type
CHCHD2 p.Ala60Val Uncertain significance ★★ ⚠ same type
CHCHD2 p.Arg51Gln Uncertain significance ★★ ⚠ same type
CHCHD2 p.Ile131Val Uncertain significance ★★ ⚠ same type
CHCHD2 p.Pro34Leu Uncertain significance ★★ ⚠ same type
CHCHD2 p.Pro39Thr Uncertain significance ★★ ⚠ same type
CHCHD2 c.300+159T>G 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/chchd2-p-ala32pro (accessed [today's date]).

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