Is CHD4 p.Pro1541Arg (c.4622C>G) pathogenic?

CHD4 p.Pro1541Arg (c.4622C>G) is classified Uncertain significance in CHD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-16). AlphaMissense: likely pathogenic (0.9245); Ultra-rare (popmax 0.0202%, amr); Associated with Inborn genetic diseases.

What condition is associated with CHD4 p.Pro1541Arg (c.4622C>G)?

CHD4 p.Pro1541Arg (c.4622C>G) is associated with Inborn genetic diseases (ClinVar).

How common is CHD4 p.Pro1541Arg (c.4622C>G) in the general population?

CHD4 p.Pro1541Arg (c.4622C>G) is ultra-rare (popmax 0.0202%, amr) (gnomAD).

What do computational predictors say about CHD4 p.Pro1541Arg (c.4622C>G)?

AlphaMissense predicts likely pathogenic (score 0.9245) — an in-silico prediction, not a clinical call.

CHD4 p.Pro1541Arg

c.4622C>G · VCV4227784

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9245 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0202%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9245	likely pathogenic
REVEL	0.679	pathogenic-leaning
SaProt	LLR -9.18	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 3,351 bp · p 0.98 · regional, not allelic
Overall
CADD	28.9	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 0.0202% Admixed American · 12/59,442 alleles

Filtering AF 0.0116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00906%

Overall 0.000746% 12/1,608,300 alleles · ultra-rare exomes 5/1,456,140 · genomes 7/152,160 · 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.Pro1541Arg
Coding: c.4622C>G
MANE Select: NM_001273
Type: single nucleotide variant
Location: chr12:6581708 (GRCh38)
Gene constraint: LOEUF 0.192 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 65.41 · 12 PDB
Residue 1541: 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.Pro1541Thr Uncertain significance ★ ⚠ same residue
CHD4 p.Pro1541Ala Uncertain significance ★★ 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-pro1541arg (accessed [today's date]).

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