Is CHCHD10 p.Pro34Ser (c.100C>T) pathogenic?

CHCHD10 p.Pro34Ser (c.100C>T) is classified Benign/Likely benign in CHCHD10 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0682); Rare (popmax 0.499%, nfe); Associated with lower motor neuron syndrome with late-adult onset.

How common is CHCHD10 p.Pro34Ser (c.100C>T) in the general population?

CHCHD10 p.Pro34Ser (c.100C>T) is rare (popmax 0.499%, nfe) (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.Pro34Ser (c.100C>T)?

AlphaMissense predicts likely benign (score 0.0682) — an in-silico prediction, not a clinical call.

CHCHD10 p.Pro34Ser

Q: What condition is associated with CHCHD10 p.Pro34Ser (c.100C>T)?

CHCHD10 p.Pro34Ser (c.100C>T) 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.100C>T · rs551521196 · VCV204291

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0682 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.499%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

lower motor neuron syndrome with late-adult onset

Computational evidence

Protein change
AlphaMissense	0.0682	likely benign
REVEL	0.621	indeterminate
SaProt	LLR -9.55	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.8	GERP -4.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 1,864 bp · p 0.66 · regional, not allelic
Overall
CADD	16.75	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 0.499% European (non-Finnish) · 5,510/1,104,018 alleles

Filtering AF 0.488% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.484%

Overall 0.406% 5,891/1,451,942 alleles · rare exomes 5,542/1,299,678 · genomes 349/152,264 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.499%	200
Remaining individualsnot grpmax-eligible	0.272%	367
Finnishnot grpmax-eligible	0.254%	394
Admixed American	0.115%	867
African / African-American	0.0846%	1,182
Ashkenazi Jewishnot grpmax-eligible	0.00791%	12,646
South Asian	0.00535%	18,699

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.Pro34Ser
Coding: c.100C>T
MANE Select: NM_213720
dbSNP: rs551521196
Type: single nucleotide variant
Location: chr22:23767535 (GRCh38)
Gene constraint: LOEUF 1.543 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.01 · 5 PDB
Residue 34: a UniProt-annotated variant site (in ftdals2); 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.Pro34Leu 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
CHCHD10 p.Ala49Val Uncertain significance ★★ ⚠ same condition
CHCHD10 p.Arg11Gly 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-pro34ser (accessed [today's date]).

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