Is SMS p.Trp292Arg (c.874T>C) pathogenic?

SMS p.Trp292Arg (c.874T>C) is classified Uncertain significance in SMS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-30). AlphaMissense: likely pathogenic (0.9976); No allele count reported in gnomAD v4.1 (AN 1,171,735).

How common is SMS p.Trp292Arg (c.874T>C) in the general population?

SMS p.Trp292Arg (c.874T>C) is no allele count reported in gnomAD v4.1 (AN 1,171,735) (gnomAD).

What do computational predictors say about SMS p.Trp292Arg (c.874T>C)?

AlphaMissense predicts likely pathogenic (score 0.9976) — an in-silico prediction, not a clinical call.

SMS p.Trp292Arg

c.874T>C · rs2519679204 · VCV2504552

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9976 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,171,735)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9976	likely pathogenic · top 4% in SMS
REVEL	0.703	pathogenic-leaning
SaProt	LLR -12.43	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 6.1	GERP 2.2, phastCons 1
Regional constraint	o/e 0.34	constrained · MANE · 22 kb · p 3.7e-21 · 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

No allele count reported in gnomAD v4.1 (AN 1,171,735). 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: SMS
Protein: p.Trp292Arg
Coding: c.874T>C
MANE Select: NM_004595
dbSNP: rs2519679204
Type: single nucleotide variant
Location: chrX:21985152 (GRCh38)
Structure: AlphaFold pLDDT 95.09 · 2 PDB
Residue 292: the pabs domain; an α-helix

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

Similar variants

SMS p.Trp292Leu Likely pathogenic ★ same residue
SMS p.Arg234Ter Pathogenic/Likely pathogenic ★★ same type
SMS p.Gly203Asp Pathogenic ★★ same type
SMS p.Gly56Ser Pathogenic ★★ ⚠ same type
SMS p.Ile196Thr Likely pathogenic ★★ same type
SMS p.Pro112Leu Pathogenic/Likely pathogenic ★★ ⚠ same type
SMS c.1061+2T>C Uncertain significance ★★ same type
SMS c.505+3A>G 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/sms-p-trp292arg (accessed [today's date]).

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