Is CHCHD2 p.Pro14Ser (c.40C>T) pathogenic?

CHCHD2 p.Pro14Ser (c.40C>T) is classified Likely benign in CHCHD2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-13). AlphaMissense: likely benign (0.0941); Rare (popmax 0.488%, sas).

How common is CHCHD2 p.Pro14Ser (c.40C>T) in the general population?

CHCHD2 p.Pro14Ser (c.40C>T) is rare (popmax 0.488%, sas) (gnomAD).

What do computational predictors say about CHCHD2 p.Pro14Ser (c.40C>T)?

AlphaMissense predicts likely benign (score 0.0941) — an in-silico prediction, not a clinical call.

CHCHD2 p.Pro14Ser

c.40C>T · rs137965562 · VCV1102651

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0941 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.488%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0941	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -9.53	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 4.7	phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 4,559 bp · p 0.078 · regional, not allelic
Overall
CADD	20.9	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 0.488% South Asian · 444/91,026 alleles

Filtering AF 0.45% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.436%

Overall 0.0454% 733/1,613,436 alleles · rare exomes 686/1,461,124 · genomes 47/152,312 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.488%	205
Ashkenazi Jewishnot grpmax-eligible	0.0473%	2,114
Remaining individualsnot grpmax-eligible	0.032%	3,123
European (non-Finnish)	0.0202%	4,956
Admixed American	0.0183%	5,450
Middle Eastern	0.0165%	6,050
African / African-American	0.00666%	15,005

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.Pro14Ser
Coding: c.40C>T
MANE Select: NM_016139
dbSNP: rs137965562
Type: single nucleotide variant
Location: chr7:56106374 (GRCh38)
Gene constraint: LOEUF 1.586 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.86 · 2 PDB
Residue 14: 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

Similar variants

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
CHCHD2 p.Ile131Val Uncertain significance ★★ ⚠ same type
CHCHD2 p.Pro34Leu Uncertain significance ★★ ⚠ same type
CHCHD2 p.Pro39Thr Uncertain significance ★★ ⚠ same type
CHCHD2 c.300+159T>G Benign ★★ 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-pro14ser (accessed [today's date]).

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