Is SMS p.Ile274Val (c.820A>G) pathogenic?

SMS p.Ile274Val (c.820A>G) is classified Uncertain significance in SMS (ClinVar, Single submitter, 1 submitter; last evaluated 2016-09-07). AlphaMissense: likely benign (0.317); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with SMS p.Ile274Val (c.820A>G)?

SMS p.Ile274Val (c.820A>G) is associated with Inborn genetic diseases (ClinVar).

How common is SMS p.Ile274Val (c.820A>G) in the general population?

SMS p.Ile274Val (c.820A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SMS p.Ile274Val (c.820A>G)?

AlphaMissense predicts likely benign (score 0.317) — an in-silico prediction, not a clinical call.

SMS p.Ile274Val

c.820A>G · rs1569354289 · VCV588239

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.317 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.317	likely benign
REVEL	0.52	indeterminate
SaProt	LLR -7.50	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 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	20.9	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

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.Ile274Val
Coding: c.820A>G
MANE Select: NM_004595
dbSNP: rs1569354289
Type: single nucleotide variant
Location: chrX:21984373 (GRCh38)
Structure: AlphaFold pLDDT 95.09 · 2 PDB
Residue 274: the pabs domain; a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SMS p.Arg234Ter Pathogenic/Likely pathogenic ★★ same condition
SMS p.Gly56Ser Pathogenic ★★ ⚠ same condition
SMS p.Pro112Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
SMS p.Lys245Asn Uncertain significance ★★ ⚠ same condition
SMS p.Ser184Asn Uncertain significance ★★ ⚠ same condition
SMS p.Ala36Val Likely benign ★★ same condition
SMS p.Glu187= Benign/Likely benign ★★ same condition
SMS p.Pro281= Benign/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-ile274val (accessed [today's date]).

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