Is CHCHD1 p.Pro4Leu (c.11C>T) pathogenic?

CHCHD1 p.Pro4Leu (c.11C>T) is classified Uncertain significance in CHCHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-13). AlphaMissense: likely benign (0.2907); Very rare (popmax 6.85e-05%).

How common is CHCHD1 p.Pro4Leu (c.11C>T) in the general population?

CHCHD1 p.Pro4Leu (c.11C>T) is very rare (popmax 6.85e-05%) (gnomAD).

What do computational predictors say about CHCHD1 p.Pro4Leu (c.11C>T)?

AlphaMissense predicts likely benign (score 0.2907) — an in-silico prediction, not a clinical call.

CHCHD1 p.Pro4Leu

c.11C>T · VCV4653222

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2907 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.85e-05%)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2907	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -10.90	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 1,108 bp · p 0.7 · regional, not allelic
Overall
CADD	25.0	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 6.85e-05%

Overall 6.85e-05% 1/1,460,896 alleles · very rare

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: CHCHD1
Protein: p.Pro4Leu
Coding: c.11C>T
MANE Select: NM_203298
Type: single nucleotide variant
Location: chr10:73782086 (GRCh38)
Gene constraint: LOEUF 1.628 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.51 · 64 PDB
Residue 4: an α-helix

Full CHCHD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHCHD1 p.Pro4Ser Uncertain significance ★ ⚠ same residue
CHCHD1 p.Ala83Val Uncertain significance ★ ⚠ same type
CHCHD1 p.Arg32Pro Uncertain significance ★ ⚠ same type
CHCHD1 p.Arg7Trp Uncertain significance ★ ⚠ same type
CHCHD1 p.Arg9Leu Uncertain significance ★ ⚠ same type
CHCHD1 p.Asn24Ser Uncertain significance ★ ⚠ same type
CHCHD1 p.Gln90Arg Uncertain significance ★ ⚠ same type
CHCHD1 p.Glu95Lys 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/chchd1-p-pro4leu (accessed [today's date]).

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