Is CHCHD10 p.Ala92Pro (c.274G>C) pathogenic?

CHCHD10 p.Ala92Pro (c.274G>C) is classified Benign/Likely benign in CHCHD10 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-28). AlphaMissense: likely benign (0.0732); Common (popmax 14.7%, amr) — too common for a highly-penetrant pathogenic allele; Associated with Inborn genetic diseases.

What condition is associated with CHCHD10 p.Ala92Pro (c.274G>C)?

CHCHD10 p.Ala92Pro (c.274G>C) is associated with Inborn genetic diseases (ClinVar).

What do computational predictors say about CHCHD10 p.Ala92Pro (c.274G>C)?

AlphaMissense predicts likely benign (score 0.0732) — an in-silico prediction, not a clinical call.

CHCHD10 p.Ala92Pro

Q: How common is CHCHD10 p.Ala92Pro (c.274G>C) in the general population?

CHCHD10 p.Ala92Pro (c.274G>C) is common (popmax 14.7%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.274G>C · rs374353973 · VCV1259100

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0732 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 14.7%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0732	likely benign
REVEL	0.006	strongly benign-leaning
SaProt	LLR -7.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.29 · evaluated, not missing
Pangolin	Δ0.21	loss · gain 0.19 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP -1.7	GERP -2.5
Regional constraint	o/e 1.03	unconstrained · MANE · 1,864 bp · p 0.66 · regional, not allelic
Overall
CADD	0.311	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 14.7% Admixed American · 3,928/26,678 alleles

Filtering AF 14.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 14.2%

Overall 8.75% 63,505/725,736 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	14.7%	7
South Asian	12.7%	8
Ashkenazi Jewishnot grpmax-eligible	10.3%	10
Middle Eastern	9.93%	10
Remaining individualsnot grpmax-eligible	9.86%	10
European (non-Finnish)	8.68%	12
East Asian	8.54%	12
Finnishnot grpmax-eligible	5.74%	17
African / African-American	2.81%	36

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: CHCHD10
Protein: p.Ala92Pro
Coding: c.274G>C
MANE Select: NM_213720
dbSNP: rs374353973
Type: single nucleotide variant
Location: chr22:23766263 (GRCh38)
Gene constraint: LOEUF 1.543 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.01 · 5 PDB
Residue 92: the 'disordered' region

Full CHCHD10 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHCHD10 p.Ala92Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
CHCHD10 p.Ala92= Likely benign same residue
CHCHD10 p.Ala31Val Uncertain significance ★★ ⚠ same condition
CHCHD10 p.Ala35Thr Uncertain significance ★★ ⚠ same condition
CHCHD10 p.Arg11Trp Uncertain significance ★★ ⚠ same condition
CHCHD10 p.Asp111Gly Uncertain significance ★★ ⚠ same condition
CHCHD10 p.Gln108Pro Uncertain significance ★★ ⚠ same condition
CHCHD10 p.Pro27Ser Uncertain significance ★★ ⚠ same condition

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/chchd10-p-ala92pro (accessed [today's date]).

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