Is CHCHD10 p.Ala35Asp (c.104C>A) pathogenic?

CHCHD10 p.Ala35Asp (c.104C>A) is classified Uncertain significance in CHCHD10 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-13). AlphaMissense: ambiguous (0.4525); Very rare (popmax 0.0029%, eas); Associated with lower motor neuron syndrome with late-adult onset.

How common is CHCHD10 p.Ala35Asp (c.104C>A) in the general population?

CHCHD10 p.Ala35Asp (c.104C>A) is very rare (popmax 0.0029%, eas) (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.Ala35Asp (c.104C>A)?

AlphaMissense predicts ambiguous (score 0.4525) — an in-silico prediction, not a clinical call.

CHCHD10 p.Ala35Asp

Q: What condition is associated with CHCHD10 p.Ala35Asp (c.104C>A)?

CHCHD10 p.Ala35Asp (c.104C>A) 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.104C>A · VCV3759599

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4525 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0029%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

lower motor neuron syndrome with late-adult onset

Computational evidence

Protein change
AlphaMissense	0.4525	ambiguous
REVEL	0.207	benign-leaning
SaProt	LLR -13.26	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP -1.6, phastCons 0.91
Regional constraint	o/e 1.03	unconstrained · MANE · 1,864 bp · p 0.66 · regional, not allelic
Overall
CADD	20.8	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 0.0029% East Asian · 1/34,514 alleles

Filtering AF 0.000195% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000128%

Overall 0.00055% 8/1,455,558 alleles · very rare exomes 8/1,303,294 · genomes 0/152,264 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0029%	34,514
Finnishnot grpmax-eligible	0.00202%	49,568
European (non-Finnish)	0.000543%	184,305

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.Ala35Asp
Coding: c.104C>A
MANE Select: NM_213720
Type: single nucleotide variant
Location: chr22:23767531 (GRCh38)
Gene constraint: LOEUF 1.543 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.01 · 5 PDB
Residue 35: 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.Ala35Thr Uncertain significance ★★ ⚠ same residue
CHCHD10 p.Ala35Ser Uncertain significance ★ ⚠ same residue
CHCHD10 p.Ala35Val 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.Ala49Val 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-ala35asp (accessed [today's date]).

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