Is CHD3 p.Pro253Ser (c.757C>T) pathogenic?

CHD3 p.Pro253Ser (c.757C>T) is classified Uncertain significance in CHD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-29). AlphaMissense: likely benign (0.096); Very rare (popmax 8.57e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CHD3 p.Pro253Ser (c.757C>T)?

CHD3 p.Pro253Ser (c.757C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CHD3 p.Pro253Ser (c.757C>T) in the general population?

CHD3 p.Pro253Ser (c.757C>T) is very rare (popmax 8.57e-05%, nfe) (gnomAD).

What do computational predictors say about CHD3 p.Pro253Ser (c.757C>T)?

AlphaMissense predicts likely benign (score 0.096) — an in-silico prediction, not a clinical call.

CHD3 p.Pro253Ser

c.757C>T · rs2544788851 · VCV2608263

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.096 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.57e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.096	likely benign
REVEL	0.45	indeterminate
SaProt	LLR -6.82	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 829 bp · p 0.013 · regional, not allelic
Overall
CADD	21.3	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 8.57e-05% European (non-Finnish) · 1/1,166,696 alleles

Overall 6.28e-05% 1/1,593,160 alleles · very rare exomes 1/1,442,018 · genomes 0/151,142 · 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: CHD3
Protein: p.Pro253Ser
Coding: c.757C>T
MANE Select: NM_001005273
dbSNP: rs2544788851
Type: single nucleotide variant
Location: chr17:7893533 (GRCh38)
Gene constraint: LOEUF 0.257 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.21
Residue 253: the 'disordered' region

Full CHD3 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

CHD3 p.Pro253Arg Uncertain significance ★★ ⚠ same residue
CHD3 p.Arg103Ter Pathogenic ★★ same condition
CHD3 p.Arg1078Gln Pathogenic/Likely pathogenic ★★ same condition
CHD3 p.Arg966Trp Pathogenic ★★ ⚠ same condition
CHD3 p.Arg985Trp Pathogenic/Likely pathogenic ★★ same condition
CHD3 p.Pro1918= Likely pathogenic ★★ same condition
CHD3 p.Arg1266Trp Uncertain significance ★★ ⚠ same condition
CHD3 p.Arg1377Cys 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/chd3-p-pro253ser (accessed [today's date]).

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