Is CHCHD10 p.Pro96Arg (c.287C>G) pathogenic?

CHCHD10 p.Pro96Arg (c.287C>G) is classified Uncertain significance in CHCHD10 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-05). AlphaMissense: likely benign (0.1427); Absent from gnomAD v4.1; Associated with lower motor neuron syndrome with late-adult onset.

How common is CHCHD10 p.Pro96Arg (c.287C>G) in the general population?

CHCHD10 p.Pro96Arg (c.287C>G) is absent from gnomAD v4.1 (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.Pro96Arg (c.287C>G)?

AlphaMissense predicts likely benign (score 0.1427) — an in-silico prediction, not a clinical call.

CHCHD10 p.Pro96Arg

Q: What condition is associated with CHCHD10 p.Pro96Arg (c.287C>G)?

CHCHD10 p.Pro96Arg (c.287C>G) 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.287C>G · rs1348340557 · VCV1488759

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1427 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lower motor neuron syndrome with late-adult onset

Computational evidence

Protein change
AlphaMissense	0.1427	likely benign
REVEL	0.123	moderately benign-leaning
SaProt	LLR -8.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.25	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 7	GERP -3.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 1,864 bp · p 0.66 · regional, not allelic
Overall
CADD	22.5	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

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: CHCHD10
Protein: p.Pro96Arg
Coding: c.287C>G
MANE Select: NM_213720
dbSNP: rs1348340557
Type: single nucleotide variant
Location: chr22:23766250 (GRCh38)
Gene constraint: LOEUF 1.543 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.01 · 5 PDB
Residue 96: 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.Pro96Thr Benign ★★ same residue
CHCHD10 p.Pro96Leu Uncertain significance ★ ⚠ same residue
CHCHD10 p.Pro96His Uncertain significance ★ ⚠ 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-pro96arg (accessed [today's date]).

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