Is SMO p.Pro698Arg (c.2093C>G) pathogenic?

SMO p.Pro698Arg (c.2093C>G) is classified Likely benign in SMO (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-03-01). AlphaMissense: likely benign (0.0721); Rare (popmax 0.359%, nfe).

How common is SMO p.Pro698Arg (c.2093C>G) in the general population?

SMO p.Pro698Arg (c.2093C>G) is rare (popmax 0.359%, nfe) (gnomAD).

What do computational predictors say about SMO p.Pro698Arg (c.2093C>G)?

AlphaMissense predicts likely benign (score 0.0721) — an in-silico prediction, not a clinical call.

SMO p.Pro698Arg

c.2093C>G · rs116640950 · VCV135260

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0721 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.359%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0721	likely benign
REVEL	0.153	moderately benign-leaning
SaProt	LLR -7.89	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 3.2	GERP 3.8, phastCons 0.97
Regional constraint	o/e 1.04	unconstrained · MANE · 1,900 bp · p 0.53 · regional, not allelic
Overall
CADD	13.8	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 0.359% European (non-Finnish) · 4,125/1,150,342 alleles

Filtering AF 0.349% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.346%

Overall 0.289% 4,505/1,557,256 alleles · rare exomes 4,255/1,404,886 · genomes 250/152,370 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.359%	279
Remaining individualsnot grpmax-eligible	0.259%	387
Admixed American	0.0971%	1,030
South Asian	0.0953%	1,049
Finnishnot grpmax-eligible	0.0883%	1,132
African / African-American	0.0504%	1,984
Middle Eastern	0.0341%	2,929
Ashkenazi Jewishnot grpmax-eligible	0.00348%	28,712

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.Pro698Arg
Coding: c.2093C>G
MANE Select: NM_005631
dbSNP: rs116640950
Type: single nucleotide variant
Location: chr7:129212180 (GRCh38)
Gene constraint: LOEUF 0.706 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.55 · 15 PDB
Residue 698: the 'disordered' region

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

Similar variants

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SMO p.Arg512Cys Uncertain significance ★★ ⚠ same type
SMO p.Arg709Gln Uncertain significance ★★ ⚠ same type
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-pro698arg (accessed [today's date]).

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