Is CHCHD10 p.Pro36Ser (c.106C>T) pathogenic?

CHCHD10 p.Pro36Ser (c.106C>T) is classified Uncertain significance in CHCHD10 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-09-18). AlphaMissense: likely benign (0.0612); Very rare (popmax 0.000361%, nfe); Associated with CHCHD10-related disorder.

How common is CHCHD10 p.Pro36Ser (c.106C>T) in the general population?

CHCHD10 p.Pro36Ser (c.106C>T) is very rare (popmax 0.000361%, nfe) (gnomAD).

What do computational predictors say about CHCHD10 p.Pro36Ser (c.106C>T)?

AlphaMissense predicts likely benign (score 0.0612) — an in-silico prediction, not a clinical call.

CHCHD10 p.Pro36Ser

Q: What condition is associated with CHCHD10 p.Pro36Ser (c.106C>T)?

CHCHD10 p.Pro36Ser (c.106C>T) is associated with CHCHD10-related disorder, lower motor neuron syndrome with late-adult onset, frontotemporal dementia and/or amyotrophic lateral sclerosis 2 (ClinVar).

c.106C>T · rs1259379217 · VCV1506273

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0612 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000361%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CHCHD10-related disorder

Computational evidence

Protein change
AlphaMissense	0.0612	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -9.38	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -4.2, phastCons 0.98
Regional constraint	o/e 1.03	unconstrained · MANE · 1,864 bp · p 0.66 · regional, not allelic
Overall
CADD	10.16	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

Grpmax group 0.000361% European (non-Finnish) · 4/1,107,516 alleles

Filtering AF 8.5e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.7e-05%

Overall 0.000274% 4/1,459,406 alleles · very rare exomes 3/1,307,248 · genomes 1/152,158 · 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.Pro36Ser
Coding: c.106C>T
MANE Select: NM_213720
dbSNP: rs1259379217
Type: single nucleotide variant
Location: chr22:23767529 (GRCh38)
Gene constraint: LOEUF 1.543 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.01 · 5 PDB
Residue 36: the 'disordered' region

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

Disease context

Also linked: lower motor neuron syndrome with late-adult onset frontotemporal dementia and/or amyotrophic lateral sclerosis 2 autosomal dominant mitochondrial myopathy with exercise intolerance

Similar variants

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
CHCHD10 p.Arg6Gly 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-pro36ser (accessed [today's date]).

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