Is SMS p.Ala264Ser (c.790G>T) pathogenic?

SMS p.Ala264Ser (c.790G>T) is classified Uncertain significance in SMS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-29). AlphaMissense: likely benign (0.1017); Very rare (popmax 0.00435%, amr).

How common is SMS p.Ala264Ser (c.790G>T) in the general population?

SMS p.Ala264Ser (c.790G>T) is very rare (popmax 0.00435%, amr) (gnomAD).

What do computational predictors say about SMS p.Ala264Ser (c.790G>T)?

AlphaMissense predicts likely benign (score 0.1017) — an in-silico prediction, not a clinical call.

SMS p.Ala264Ser

c.790G>T · rs755650468 · VCV2812943

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1017 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00435%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1017	likely benign
REVEL	0.279	benign-leaning
SaProt	LLR -7.75	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP 2.2, phastCons 1
Regional constraint	o/e 0.34	constrained · MANE · 22 kb · p 3.7e-21 · regional, not allelic
Overall
CADD	22.4	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 0.00435% Admixed American · 2/45,984 alleles

Filtering AF 0.000721% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00027%

Overall 0.000185% 2/1,082,037 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.Ala264Ser
Coding: c.790G>T
MANE Select: NM_004595
dbSNP: rs755650468
Type: single nucleotide variant
Location: chrX:21984343 (GRCh38)
Structure: AlphaFold pLDDT 95.09 · 2 PDB
Residue 264: the pabs domain; an α-helix

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

Similar variants

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
SMS c.661-4G>A 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-ala264ser (accessed [today's date]).

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