Is SMO p.Pro641Ala (c.1921C>G) pathogenic?

SMO p.Pro641Ala (c.1921C>G) is classified Uncertain significance in SMO (ClinVar, Single submitter, 2 submitters; last evaluated 2023-06-08). AlphaMissense: likely benign (0.1288); Ultra-rare (popmax 0.0822%, nfe).

How common is SMO p.Pro641Ala (c.1921C>G) in the general population?

SMO p.Pro641Ala (c.1921C>G) is ultra-rare (popmax 0.0822%, nfe) (gnomAD).

What do computational predictors say about SMO p.Pro641Ala (c.1921C>G)?

AlphaMissense predicts likely benign (score 0.1288) — an in-silico prediction, not a clinical call.

SMO p.Pro641Ala

c.1921C>G · rs146200641 · VCV135574

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1288 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0822%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1288	likely benign
REVEL	0.833	moderately pathogenic-leaning
SaProt	LLR -7.51	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 3.8, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,900 bp · p 0.53 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0822% European (non-Finnish) · 970/1,180,020 alleles

Filtering AF 0.0778% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0762%

Overall 0.0657% 1,061/1,613,958 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0822%	1,217
Remaining individualsnot grpmax-eligible	0.0752%	1,329
Admixed American	0.045%	2,222
Finnishnot grpmax-eligible	0.0125%	8,002
African / African-American	0.012%	8,322

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: SMO
Protein: p.Pro641Ala
Coding: c.1921C>G
MANE Select: NM_005631
dbSNP: rs146200641
Type: single nucleotide variant
Location: chr7:129211755 (GRCh38)
Gene constraint: LOEUF 0.706 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.55 · 15 PDB
Residue 641: the 'required for interaction with prkaca' region

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

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SMO p.Asp201Val Uncertain significance ★★ ⚠ same type
SMO p.Gly598Val Uncertain significance ★★ ⚠ same type
SMO p.Leu197= Uncertain significance ★★ same type
SMO p.Val129Ile Uncertain significance ★★ ⚠ same type
SMO p.Val195Met 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/smo-p-pro641ala (accessed [today's date]).

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