Is CHML p.Arg403His (c.1208G>A) pathogenic?

CHML p.Arg403His (c.1208G>A) is classified Uncertain significance in CHML (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-18). AlphaMissense: likely benign (0.091); Very rare (popmax 0.00667%, amr).

How common is CHML p.Arg403His (c.1208G>A) in the general population?

CHML p.Arg403His (c.1208G>A) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about CHML p.Arg403His (c.1208G>A)?

AlphaMissense predicts likely benign (score 0.091) — an in-silico prediction, not a clinical call.

CHML p.Arg403His

c.1208G>A · VCV3267057

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.091 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.091	likely benign
REVEL	0.243	benign-leaning
SaProt	LLR -11.39	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP 0.92, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 1,967 bp · p 0.34 · regional, not allelic
Overall
CADD	23.2	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 0.00667% Admixed American · 4/59,960 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000821% 12/1,461,564 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,990
South Asian	0.00439%	22,763
European (non-Finnish)	0.000339%	294,961

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: CHML
Protein: p.Arg403His
Coding: c.1208G>A
MANE Select: NM_001381853
Type: single nucleotide variant
Location: chr1:241634559 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.77

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

Similar variants

CHML p.Arg403Cys Uncertain significance ★ ⚠ same residue
CHML p.Arg403Pro Uncertain significance ★ ⚠ same residue
OPN3 p.Leu80= Benign ★★ same type
CHML p.Ala105Thr Uncertain significance ★ ⚠ same type
CHML p.Ala105Val Uncertain significance ★ ⚠ same type
CHML p.Ala24Gly Uncertain significance ★ ⚠ same type
CHML p.Ala267Pro Uncertain significance ★ ⚠ same type
CHML p.Ala26Pro 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/chml-p-arg403his (accessed [today's date]).

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