Is SMS p.Glu207Ala (c.620A>C) pathogenic?

SMS p.Glu207Ala (c.620A>C) is classified Uncertain significance in SMS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-01). AlphaMissense: likely pathogenic (0.8365); Very rare (popmax 0.00217%, amr); Associated with SMS-related disorder.

What condition is associated with SMS p.Glu207Ala (c.620A>C)?

SMS p.Glu207Ala (c.620A>C) is associated with SMS-related disorder (ClinVar).

How common is SMS p.Glu207Ala (c.620A>C) in the general population?

SMS p.Glu207Ala (c.620A>C) is very rare (popmax 0.00217%, amr) (gnomAD).

What do computational predictors say about SMS p.Glu207Ala (c.620A>C)?

AlphaMissense predicts likely pathogenic (score 0.8365) — an in-silico prediction, not a clinical call.

SMS p.Glu207Ala

c.620A>C · rs1222075173 · VCV2633550

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8365 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00217%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

SMS-related disorder

Computational evidence

Protein change
AlphaMissense	0.8365	likely pathogenic
REVEL	0.931	moderately pathogenic-leaning
SaProt	LLR -13.94	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.44 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.34	constrained · MANE · 22 kb · p 3.7e-21 · regional, not allelic
Overall
CADD	25.5	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

Grpmax group 0.00217% Admixed American · 1/46,017 alleles

Overall 9.12e-05% 1/1,096,419 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.Glu207Ala
Coding: c.620A>C
MANE Select: NM_004595
dbSNP: rs1222075173
Type: single nucleotide variant
Location: chrX:21978074 (GRCh38)
Structure: AlphaFold pLDDT 95.09 · 2 PDB
Residue 207: the pabs domain; an α-helix

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.Glu37Asp 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-glu207ala (accessed [today's date]).

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