Is CHCHD2 p.Met59Val (c.175A>G) pathogenic?

CHCHD2 p.Met59Val (c.175A>G) is classified Uncertain significance in CHCHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-15). AlphaMissense: likely pathogenic (0.5873); Very rare (popmax 0.00401%, afr).

How common is CHCHD2 p.Met59Val (c.175A>G) in the general population?

CHCHD2 p.Met59Val (c.175A>G) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about CHCHD2 p.Met59Val (c.175A>G)?

AlphaMissense predicts likely pathogenic (score 0.5873) — an in-silico prediction, not a clinical call.

CHCHD2 p.Met59Val

c.175A>G · VCV3664998

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5873 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.5873	likely pathogenic
REVEL	0.539	indeterminate
SaProt	LLR -10.80	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 4,559 bp · p 0.078 · regional, not allelic
Overall
CADD	23.2	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

Grpmax group 0.00401% African / African-American · 3/74,896 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000248% 4/1,613,238 alleles · very rare exomes 2/1,461,120 · genomes 2/152,118 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,965
South Asian	0.0011%	91,056

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.Met59Val
Coding: c.175A>G
MANE Select: NM_016139
Type: single nucleotide variant
Location: chr7:56104351 (GRCh38)
Gene constraint: LOEUF 1.586 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.86 · 2 PDB
Residue 59: a β-strand

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

Similar variants

CHCHD2 c.446-9T>A Uncertain significance ★★ same type
CHCHD2 p.Ala32Thr 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-met59val (accessed [today's date]).

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