Is CHML p.Trp47Arg (c.139T>C) pathogenic?

CHML p.Trp47Arg (c.139T>C) is classified Uncertain significance in CHML (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: likely pathogenic (0.9712); Absent from gnomAD v4.1.

How common is CHML p.Trp47Arg (c.139T>C) in the general population?

CHML p.Trp47Arg (c.139T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CHML p.Trp47Arg (c.139T>C)?

AlphaMissense predicts likely pathogenic (score 0.9712) — an in-silico prediction, not a clinical call.

CHML p.Trp47Arg

c.139T>C · VCV4653435

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9712 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9712	likely pathogenic · top 1% in CHML
REVEL	0.455	indeterminate
SaProt	LLR -12.25	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 1,967 bp · p 0.34 · regional, not allelic
Overall
CADD	28.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CHML
Protein: p.Trp47Arg
Coding: c.139T>C
MANE Select: NM_001381853
Type: single nucleotide variant
Location: chr1:241635628 (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

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
CHML p.Ala2Val Uncertain significance ★ ⚠ same type
CHML p.Ala627Thr 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-trp47arg (accessed [today's date]).

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