Is CHCHD10 p.Arg3Pro (c.8G>C) pathogenic?

CHCHD10 p.Arg3Pro (c.8G>C) is classified Uncertain significance in CHCHD10 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-23). AlphaMissense: ambiguous (0.3641); Very rare (popmax 0.00124%, sas); Associated with lower motor neuron syndrome with late-adult onset.

How common is CHCHD10 p.Arg3Pro (c.8G>C) in the general population?

CHCHD10 p.Arg3Pro (c.8G>C) is very rare (popmax 0.00124%, sas) (gnomAD).

How is Lower motor neuron syndrome with late-adult onset inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CHCHD10 p.Arg3Pro (c.8G>C)?

AlphaMissense predicts ambiguous (score 0.3641) — an in-silico prediction, not a clinical call.

CHCHD10 p.Arg3Pro

Q: What condition is associated with CHCHD10 p.Arg3Pro (c.8G>C)?

CHCHD10 p.Arg3Pro (c.8G>C) is associated with lower motor neuron syndrome with late-adult onset, frontotemporal dementia and/or amyotrophic lateral sclerosis 2, autosomal dominant mitochondrial myopathy with exercise intolerance (ClinVar).

c.8G>C · rs766426370 · VCV1003466

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3641 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00124%, sas)

Conditions

lower motor neuron syndrome with late-adult onset

Computational evidence

Protein change
AlphaMissense	0.3641	ambiguous
REVEL	0.31	indeterminate
SaProt	LLR -12.22	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 1.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 1,864 bp · p 0.66 · regional, not allelic
Overall
CADD	27.8	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 0.00124% South Asian · 1/80,884 alleles

Overall 6.61e-05% 1/1,513,504 alleles · very rare exomes 1/1,361,372 · genomes 0/152,132 · 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: CHCHD10
Protein: p.Arg3Pro
Coding: c.8G>C
MANE Select: NM_213720
dbSNP: rs766426370
Type: single nucleotide variant
Location: chr22:23767867 (GRCh38)
Gene constraint: LOEUF 1.543 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.01 · 5 PDB
Residue 3: the 'disordered' region

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

Disease context

lower motor neuron syndrome with late-adult onset — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: frontotemporal dementia and/or amyotrophic lateral sclerosis 2 autosomal dominant mitochondrial myopathy with exercise intolerance

For Lower motor neuron syndrome with late-adult onset (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

CHCHD10 p.Arg3Gln Uncertain significance ★ ⚠ same residue
CHCHD10 p.Arg3Leu Uncertain significance ★ ⚠ same residue
CHCHD10 p.Arg3= Likely benign ★ same residue
CHCHD10 p.Ser59Leu Pathogenic/Likely pathogenic ★★ same condition
CHCHD10 c.262-3C>G Uncertain significance ★★ same condition
CHCHD10 c.409+1G>A Uncertain significance ★★ same condition
CHCHD10 p.Ala31Val Uncertain significance ★★ ⚠ same condition
CHCHD10 p.Ala35Thr 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-arg3pro (accessed [today's date]).

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