Is CHM p.Asp280His (c.838G>C) pathogenic?

CHM p.Asp280His (c.838G>C) is classified Uncertain significance in CHM (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-25). AlphaMissense: likely pathogenic (0.8936); Ultra-rare (popmax 0.0262%, afr); Associated with Inborn genetic diseases.

What condition is associated with CHM p.Asp280His (c.838G>C)?

CHM p.Asp280His (c.838G>C) is associated with Inborn genetic diseases (ClinVar).

How common is CHM p.Asp280His (c.838G>C) in the general population?

CHM p.Asp280His (c.838G>C) is ultra-rare (popmax 0.0262%, afr) (gnomAD).

What do computational predictors say about CHM p.Asp280His (c.838G>C)?

AlphaMissense predicts likely pathogenic (score 0.8936) — an in-silico prediction, not a clinical call.

CHM p.Asp280His

c.838G>C · rs139655348 · VCV1431743

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8936 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0262%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8936	likely pathogenic
REVEL	0.737	pathogenic-leaning
SaProt	LLR -17.14	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 2.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 183 kb · p 0.28 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0262% African / African-American · 15/57,329 alleles

Filtering AF 0.0161% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.013%

Overall 0.00132% 16/1,209,085 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0262%	3,822
Remaining individualsnot grpmax-eligible	0.0021%	47,529

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: CHM
Protein: p.Asp280His
Coding: c.838G>C
MANE Select: NM_000390
dbSNP: rs139655348
Type: single nucleotide variant
Location: chrX:85957957 (GRCh38)
Structure: AlphaFold pLDDT 81.05

Full CHM 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

CHM p.Asp280Gly Uncertain significance ★ ⚠ same residue
CHM p.Ala123Val Uncertain significance ★★ ⚠ same condition
CHM p.Ala133Thr Uncertain significance ★★ ⚠ same condition
CHM p.Ala166Glu Uncertain significance ★★ ⚠ same condition
CHM p.Arg555Thr Uncertain significance ★★ ⚠ same condition
CHM p.Asn553Asp Uncertain significance ★★ ⚠ same condition
CHM p.Asn610Asp Uncertain significance ★★ ⚠ same condition
CHM p.Gln119Arg 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/chm-p-asp280his (accessed [today's date]).

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