Is CHD4 p.Pro251Ala (c.751C>G) pathogenic?

CHD4 p.Pro251Ala (c.751C>G) is classified Conflicting classifications of pathogenicity in CHD4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-02-20). AlphaMissense: likely benign (0.0542); Ultra-rare (popmax 0.0483%, amr); Associated with Inborn genetic diseases.

What condition is associated with CHD4 p.Pro251Ala (c.751C>G)?

CHD4 p.Pro251Ala (c.751C>G) is associated with Inborn genetic diseases (ClinVar).

How common is CHD4 p.Pro251Ala (c.751C>G) in the general population?

CHD4 p.Pro251Ala (c.751C>G) is ultra-rare (popmax 0.0483%, amr) (gnomAD).

What do computational predictors say about CHD4 p.Pro251Ala (c.751C>G)?

AlphaMissense predicts likely benign (score 0.0542) — an in-silico prediction, not a clinical call.

CHD4 p.Pro251Ala

c.751C>G · rs767257985 · VCV1607967

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0542 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0483%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0542	likely benign
REVEL	0.28	benign-leaning
SaProt	LLR -6.93	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 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 1,073 bp · p 0.009 · regional, not allelic
Overall
CADD	23.6	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 0.0483% Admixed American · 29/60,012 alleles

Filtering AF 0.0345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0299%

Overall 0.0018% 29/1,614,140 alleles · ultra-rare exomes 29/1,461,876 · genomes 0/152,264 · 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: CHD4
Protein: p.Pro251Ala
Coding: c.751C>G
MANE Select: NM_001273
dbSNP: rs767257985
Type: single nucleotide variant
Location: chr12:6601337 (GRCh38)
Gene constraint: LOEUF 0.192 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 65.41 · 12 PDB
Residue 251: the 'disordered' region

Full CHD4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHD4 p.Pro251His Uncertain significance ★★ ⚠ same residue
CHD4 p.Pro251= Likely benign ★ same residue
CHD4 p.Arg1173Gln Pathogenic/Likely pathogenic ★★ same condition
CHD4 p.Ala1718Val Uncertain significance ★★ ⚠ same condition
CHD4 p.Arg1288Trp Uncertain significance ★★ ⚠ same condition
CHD4 p.Arg611His Uncertain significance ★★ ⚠ same condition
CHD4 p.Arg836Cys Uncertain significance ★★ ⚠ same condition
CHD4 p.Asp1395Glu 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/chd4-p-pro251ala (accessed [today's date]).

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