Is CHDH p.Ser42Arg (c.126C>G) pathogenic?

CHDH p.Ser42Arg (c.126C>G) is classified Uncertain significance in CHDH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-18). AlphaMissense: likely pathogenic (0.6596); Very rare (popmax 0.00343%, amr).

How common is CHDH p.Ser42Arg (c.126C>G) in the general population?

CHDH p.Ser42Arg (c.126C>G) is very rare (popmax 0.00343%, amr) (gnomAD).

What do computational predictors say about CHDH p.Ser42Arg (c.126C>G)?

AlphaMissense predicts likely pathogenic (score 0.6596) — an in-silico prediction, not a clinical call.

CHDH p.Ser42Arg

c.126C>G · VCV3492142

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6596 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00343%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6596	likely pathogenic
REVEL	0.284	benign-leaning
SaProt	LLR -10.02	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	Δ0.24	donor gain, 1 bp away · masked 0 · deltas
Pangolin	Δ0.52	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.72	GERP -3.6, phastCons 0.99
Regional constraint	o/e 0.99	unconstrained · MANE · 6,228 bp · p 0.86 · regional, not allelic
Overall
CADD	21.5	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 0.00343% Admixed American · 2/58,390 alleles

Filtering AF 0.000568% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000213%

Overall 0.000126% 2/1,589,144 alleles · very rare

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.Ser42Arg
Coding: c.126C>G
MANE Select: NM_018397
Type: single nucleotide variant
Location: chr3:53823883 (GRCh38)
Gene constraint: LOEUF 1.092 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.84
Residue 42: a binding site

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

Similar variants

CHDH p.Ser42Gly Uncertain significance ★ ⚠ same residue
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

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-ser42arg (accessed [today's date]).

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