Is SMS p.Glu37Asp (c.111G>T) pathogenic?

SMS p.Glu37Asp (c.111G>T) is classified Uncertain significance in SMS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-21). AlphaMissense: likely benign (0.2761); Very rare (popmax 0.000112%, nfe); Associated with SMS-related disorder.

What condition is associated with SMS p.Glu37Asp (c.111G>T)?

SMS p.Glu37Asp (c.111G>T) is associated with SMS-related disorder (ClinVar).

How common is SMS p.Glu37Asp (c.111G>T) in the general population?

SMS p.Glu37Asp (c.111G>T) is very rare (popmax 0.000112%, nfe) (gnomAD).

What do computational predictors say about SMS p.Glu37Asp (c.111G>T)?

AlphaMissense predicts likely benign (score 0.2761) — an in-silico prediction, not a clinical call.

SMS p.Glu37Asp

c.111G>T · rs762162684 · VCV2630057

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2761 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

SMS-related disorder

Computational evidence

Protein change
AlphaMissense	0.2761	likely benign
REVEL	0.48	indeterminate
SaProt	LLR -7.72	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP -0.82, phastCons 1
Regional constraint	o/e 0.38	unconstrained · MANE · 31 kb · p 1.5e-06 · regional, not allelic
Overall
CADD	18.69	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000112% European (non-Finnish) · 1/894,272 alleles

Overall 9.12e-05% 1/1,096,837 alleles · very rare

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: SMS
Protein: p.Glu37Asp
Coding: c.111G>T
MANE Select: NM_004595
dbSNP: rs762162684
Type: single nucleotide variant
Location: chrX:21967257 (GRCh38)
Structure: AlphaFold pLDDT 95.09 · 2 PDB
Residue 37: 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.Ile253Arg 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-glu37asp (accessed [today's date]).

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