Is CHCHD2 p.Pro2Leu (c.5C>T) pathogenic?

CHCHD2 p.Pro2Leu (c.5C>T) is classified Benign/Likely benign in CHCHD2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-24). AlphaMissense: likely pathogenic (0.7181); Low-frequency (popmax 1.05%, eas).

How common is CHCHD2 p.Pro2Leu (c.5C>T) in the general population?

CHCHD2 p.Pro2Leu (c.5C>T) is low-frequency (popmax 1.05%, eas) (gnomAD).

What do computational predictors say about CHCHD2 p.Pro2Leu (c.5C>T)?

AlphaMissense predicts likely pathogenic (score 0.7181) — an in-silico prediction, not a clinical call.

CHCHD2 p.Pro2Leu

c.5C>T · rs142444896 · VCV703422

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7181 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.05%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7181	likely pathogenic
REVEL	0.275	benign-leaning
SaProt	LLR -12.64	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.2	phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 4,559 bp · p 0.078 · regional, not allelic
Overall
CADD	24.1	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 1.05% East Asian · 473/44,856 alleles

Filtering AF 0.976% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.945%

Overall 0.425% 6,861/1,613,528 alleles · low-frequency exomes 5,746/1,461,262 · genomes 1,115/152,266 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	8.47%	12
East Asiangrpmax	1.05%	95
Remaining individualsnot grpmax-eligible	0.341%	293
European (non-Finnish)	0.0626%	1,596
Middle Eastern	0.033%	3,029
South Asian	0.0297%	3,372
African / African-American	0.004%	25,010

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro2Leu
Coding: c.5C>T
MANE Select: NM_016139
dbSNP: rs142444896
Type: single nucleotide variant
Location: chr7:56106409 (GRCh38)
Gene constraint: LOEUF 1.586 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.86 · 2 PDB
Residue 2: 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-pro2leu (accessed [today's date]).

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