Is CHCHD2 p.Pro34Leu (c.101C>T) pathogenic?

CHCHD2 p.Pro34Leu (c.101C>T) is classified Uncertain significance in CHCHD2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-11). AlphaMissense: likely benign (0.0893); Ultra-rare (popmax 0.0252%, amr); Associated with Parkinson disease 22, autosomal dominant.

What condition is associated with CHCHD2 p.Pro34Leu (c.101C>T)?

CHCHD2 p.Pro34Leu (c.101C>T) is associated with Parkinson disease 22, autosomal dominant (ClinVar).

How common is CHCHD2 p.Pro34Leu (c.101C>T) in the general population?

CHCHD2 p.Pro34Leu (c.101C>T) is ultra-rare (popmax 0.0252%, amr) (gnomAD).

How is Hereditary late-onset Parkinson disease inherited?

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

What do computational predictors say about CHCHD2 p.Pro34Leu (c.101C>T)?

AlphaMissense predicts likely benign (score 0.0893) — an in-silico prediction, not a clinical call.

CHCHD2 p.Pro34Leu

c.101C>T · rs371198317 · VCV948138

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0893 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0252%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Parkinson disease 22, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.0893	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -9.80	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 5.6	phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 4,559 bp · p 0.078 · regional, not allelic
Overall
CADD	22.1	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 0.0252% Admixed American · 15/59,608 alleles

Filtering AF 0.0155% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0125%

Overall 0.00925% 149/1,610,074 alleles · ultra-rare exomes 126/1,457,834 · genomes 23/152,240 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0252%	3,974
Remaining individualsnot grpmax-eligible	0.0161%	6,224
European (non-Finnish)	0.0104%	9,662
African / African-American	0.00267%	37,451

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: CHCHD2
Protein: p.Pro34Leu
Coding: c.101C>T
MANE Select: NM_016139
dbSNP: rs371198317
Type: single nucleotide variant
Location: chr7:56104425 (GRCh38)
Gene constraint: LOEUF 1.586 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.86 · 2 PDB
Residue 34: a UniProt-annotated variant site (may influence risk for lewy body disorders); the 'disordered' region

Full CHCHD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Parkinson disease 22, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary late-onset Parkinson disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

CHCHD2 p.Thr61Ile Pathogenic ★ same condition
CHCHD2 p.Arg145Gln Uncertain significance ★ ⚠ same condition
CHCHD2 p.Gln52His Uncertain significance ★ ⚠ same condition
CHCHD2 c.300+5G>A Pathogenic same condition
CHCHD2 c.446-9T>A Uncertain significance ★★ same type
CHCHD2 p.Ala32Thr Uncertain significance ★★ ⚠ same type
CHCHD2 p.Ala60Val Uncertain significance ★★ ⚠ same type
CHCHD2 p.Arg51Gln Uncertain significance ★★ ⚠ same type

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/chchd2-p-pro34leu (accessed [today's date]).

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