Is SMS p.Ile253Arg (c.758T>G) pathogenic?

SMS p.Ile253Arg (c.758T>G) is classified Uncertain significance in SMS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-06). AlphaMissense: likely pathogenic (0.8178); Absent from gnomAD v4.1; Associated with SMS-related disorder.

What condition is associated with SMS p.Ile253Arg (c.758T>G)?

SMS p.Ile253Arg (c.758T>G) is associated with SMS-related disorder (ClinVar).

How common is SMS p.Ile253Arg (c.758T>G) in the general population?

SMS p.Ile253Arg (c.758T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SMS p.Ile253Arg (c.758T>G)?

AlphaMissense predicts likely pathogenic (score 0.8178) — an in-silico prediction, not a clinical call.

SMS p.Ile253Arg

c.758T>G · rs2519678012 · VCV2633812

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8178 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

SMS-related disorder

Computational evidence

Protein change
AlphaMissense	0.8178	likely pathogenic
REVEL	0.654	pathogenic-leaning
SaProt	LLR -11.73	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 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.34	constrained · MANE · 22 kb · p 3.7e-21 · regional, not allelic
Overall
CADD	24.7	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: SMS
Protein: p.Ile253Arg
Coding: c.758T>G
MANE Select: NM_004595
dbSNP: rs2519678012
Type: single nucleotide variant
Location: chrX:21984311 (GRCh38)
Structure: AlphaFold pLDDT 95.09 · 2 PDB
Residue 253: the pabs domain; a β-strand

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

Disease context

SMS-related disorder

Similar variants

SMS p.Arg116Ter Likely pathogenic ★ same condition
SMS p.Glu207Ala Uncertain significance ★ ⚠ same condition
SMS p.Glu37Asp Uncertain significance ★ ⚠ same condition
SMS c.661-1C>T Likely pathogenic same condition
SMS p.Gly67Val Likely pathogenic same condition
SMS p.Glu340= Likely benign same condition
SMS p.Thr322= Likely benign same condition
SMS p.Tyr312= Likely benign 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/sms-p-ile253arg (accessed [today's date]).

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