Is CHD3 p.Pro538Ala (c.1612C>G) pathogenic?

CHD3 p.Pro538Ala (c.1612C>G) is classified Uncertain significance in CHD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-03-03). AlphaMissense: likely benign (0.0507); Very rare (popmax 0.00935%, afr).

How common is CHD3 p.Pro538Ala (c.1612C>G) in the general population?

CHD3 p.Pro538Ala (c.1612C>G) is very rare (popmax 0.00935%, afr) (gnomAD).

What do computational predictors say about CHD3 p.Pro538Ala (c.1612C>G)?

AlphaMissense predicts likely benign (score 0.0507) — an in-silico prediction, not a clinical call.

CHD3 p.Pro538Ala

c.1612C>G · rs761557613 · VCV1315418

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0507 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00935%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0507	likely benign
REVEL	0.303	indeterminate
SaProt	LLR -6.28	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP -3.5, phastCons 0.53
Regional constraint	o/e 1.31	unconstrained · MANE · 36 bp · p 0.18 · regional, not allelic
Overall
CADD	4.816	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00935% African / African-American · 7/74,864 alleles

Filtering AF 0.00438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.000496% 8/1,613,530 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00935%	10,695
European (non-Finnish)	8.48e-05%	1,179,645

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: CHD3
Protein: p.Pro538Ala
Coding: c.1612C>G
MANE Select: NM_001005273
dbSNP: rs761557613
Type: single nucleotide variant
Location: chr17:7895447 (GRCh38)
Gene constraint: LOEUF 0.257 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.21
Residue 538: the chromo 1 domain; the 'disordered' region; a UniProt-annotated variant site (in snibcps)

Full CHD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHD3 p.Pro538Arg Uncertain significance ★ ⚠ same residue
CHD3 p.Pro538Leu Uncertain significance ★ ⚠ same residue
CHD3 p.Pro538fs Pathogenic ★ same residue
CHD3 c.4073-2A>C Likely pathogenic ★★ same type
CHD3 p.Arg103Ter Pathogenic ★★ same type
CHD3 p.Arg1078Gln Pathogenic/Likely pathogenic ★★ same type
CHD3 p.Arg1121Pro Pathogenic/Likely pathogenic ★★ same type
CHD3 p.Arg1169Gln Pathogenic/Likely pathogenic ★★ 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/chd3-p-pro538ala (accessed [today's date]).

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