Is CHDH p.Glu375Asp (c.1125G>C) pathogenic?

CHDH p.Glu375Asp (c.1125G>C) is classified Likely benign in CHDH (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-20). AlphaMissense: likely benign (0.1673); Ultra-rare (popmax 0.0484%, sas).

How common is CHDH p.Glu375Asp (c.1125G>C) in the general population?

CHDH p.Glu375Asp (c.1125G>C) is ultra-rare (popmax 0.0484%, sas) (gnomAD).

What do computational predictors say about CHDH p.Glu375Asp (c.1125G>C)?

AlphaMissense predicts likely benign (score 0.1673) — an in-silico prediction, not a clinical call.

CHDH p.Glu375Asp

c.1125G>C · rs376011719 · VCV3144272

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1673 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0484%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1673	likely benign
REVEL	0.055	moderately benign-leaning
SaProt	LLR -7.96	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.21	donor gain, 25 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -2.9	GERP -3.2
Regional constraint	o/e 0.99	unconstrained · MANE · 6,228 bp · p 0.86 · regional, not allelic
Overall
CADD	0.025	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 0.0484% South Asian · 43/88,884 alleles

Filtering AF 0.0368% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0329%

Overall 0.00481% 77/1,600,118 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0484%	2,067
Remaining individualsnot grpmax-eligible	0.0113%	8,841
Admixed American	0.00341%	29,317
European (non-Finnish)	0.00213%	46,912

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: CHDH
Protein: p.Glu375Asp
Coding: c.1125G>C
MANE Select: NM_018397
dbSNP: rs376011719
Type: single nucleotide variant
Location: chr3:53819670 (GRCh38)
Gene constraint: LOEUF 1.092 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.84

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

Similar variants

CHDH p.Pro396Leu Uncertain significance ★★ ⚠ same type
CHDH c.704-3C>T Benign ★★ same type
CHDH p.Gly235= Benign ★★ same type
CHDH p.Val45= Benign ★★ same type
CHDH p.Ala13Val Uncertain significance ★ ⚠ same type
CHDH p.Ala170Thr Uncertain significance ★ ⚠ same type
CHDH p.Ala177Thr Uncertain significance ★ ⚠ same type
CHDH p.Ala240Val Uncertain significance ★ ⚠ 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/chdh-p-glu375asp (accessed [today's date]).

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