Is SMO p.Val657Phe (c.1969G>T) pathogenic?

SMO p.Val657Phe (c.1969G>T) is classified Uncertain significance in SMO (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-25). AlphaMissense: likely benign (0.161); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with SMO p.Val657Phe (c.1969G>T)?

SMO p.Val657Phe (c.1969G>T) is associated with Inborn genetic diseases (ClinVar).

How common is SMO p.Val657Phe (c.1969G>T) in the general population?

SMO p.Val657Phe (c.1969G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SMO p.Val657Phe (c.1969G>T)?

AlphaMissense predicts likely benign (score 0.161) — an in-silico prediction, not a clinical call.

SMO p.Val657Phe

c.1969G>T · VCV3446385

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.161 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,588,806)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.161	likely benign
REVEL	0.515	indeterminate
SaProt	LLR -7.67	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 12	GERP 3.7, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,900 bp · p 0.53 · regional, not allelic
Overall
CADD	25.9	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

No allele count reported in gnomAD v4.1 (AN 1,588,806). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: SMO
Protein: p.Val657Phe
Coding: c.1969G>T
MANE Select: NM_005631
Type: single nucleotide variant
Location: chr7:129212056 (GRCh38)
Gene constraint: LOEUF 0.706 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.55 · 15 PDB

Full SMO 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

SMO p.Arg512Cys Uncertain significance ★★ ⚠ same condition
SMO p.Asp201Val Uncertain significance ★★ ⚠ same condition
SMO p.Gly598Val Uncertain significance ★★ ⚠ same condition
SMO p.Val195Met Uncertain significance ★★ ⚠ same condition
SMO p.Asp597= Likely benign ★★ same condition
SMO p.Ala604Thr Uncertain significance ★ ⚠ same condition
SMO p.Ala686Ser Uncertain significance ★ ⚠ same condition
SMO p.Ala752Thr Uncertain significance ★ ⚠ 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/smo-p-val657phe (accessed [today's date]).

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