Is CHM p.Cys416Arg (c.1246T>C) pathogenic?

CHM p.Cys416Arg (c.1246T>C) is classified Uncertain significance in CHM (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-17). AlphaMissense: likely pathogenic (0.9902); Absent from gnomAD v4.1.

How common is CHM p.Cys416Arg (c.1246T>C) in the general population?

CHM p.Cys416Arg (c.1246T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CHM p.Cys416Arg (c.1246T>C)?

AlphaMissense predicts likely pathogenic (score 0.9902) — an in-silico prediction, not a clinical call.

CHM p.Cys416Arg

c.1246T>C · rs1926267075 · VCV933944

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9902 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,116,930)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9902	likely pathogenic · top 3% in CHM
REVEL	0.41	indeterminate
SaProt	LLR -13.94	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 183 kb · p 0.28 · regional, not allelic
Overall
CADD	26.3	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

No allele count reported in gnomAD v4.1 (AN 1,116,930). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CHM
Protein: p.Cys416Arg
Coding: c.1246T>C
MANE Select: NM_000390
dbSNP: rs1926267075
Type: single nucleotide variant
Location: chrX:85901187 (GRCh38)
Structure: AlphaFold pLDDT 81.05

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

Similar variants

CHM p.Cys416= Likely benign ★ same residue
CHM c.116+1G>A Pathogenic/Likely pathogenic ★★ same type
CHM c.116+1G>T Pathogenic/Likely pathogenic ★★ same type
CHM c.1166+1G>A Pathogenic ★★ same type
CHM c.1166+1G>C Pathogenic ★★ same type
CHM c.1167-2A>G Pathogenic ★★ same type
CHM c.1244+1G>A Pathogenic ★★ same type
CHM c.1244+2T>A Pathogenic/Likely pathogenic ★★ 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/chm-p-cys416arg (accessed [today's date]).

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