Is SMO p.Arg421Gln (c.1262G>A) pathogenic?

SMO p.Arg421Gln (c.1262G>A) is classified Uncertain significance in SMO (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-02). AlphaMissense: likely benign (0.2017); Very rare (popmax 0.00534%, afr); Associated with Inborn genetic diseases.

What condition is associated with SMO p.Arg421Gln (c.1262G>A)?

SMO p.Arg421Gln (c.1262G>A) is associated with Inborn genetic diseases (ClinVar).

How common is SMO p.Arg421Gln (c.1262G>A) in the general population?

SMO p.Arg421Gln (c.1262G>A) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about SMO p.Arg421Gln (c.1262G>A)?

AlphaMissense predicts likely benign (score 0.2017) — an in-silico prediction, not a clinical call.

SMO p.Arg421Gln

c.1262G>A · rs968935409 · VCV3166599

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2017 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2017	likely benign
REVEL	0.749	pathogenic-leaning
SaProt	LLR -8.90	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 7.5	GERP 3.7, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 7,113 bp · p 1.7e-08 · regional, not allelic
Overall
CADD	28.7	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 0.00534% African / African-American · 4/74,930 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000558% 9/1,614,030 alleles · very rare exomes 6/1,461,822 · genomes 3/152,208 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,732
South Asian	0.0011%	91,076
European (non-Finnish)	0.000339%	295,009

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.Arg421Gln
Coding: c.1262G>A
MANE Select: NM_005631
dbSNP: rs968935409
Type: single nucleotide variant
Location: chr7:129206585 (GRCh38)
Gene constraint: LOEUF 0.706 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.55 · 15 PDB
Residue 421: an α-helix

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-arg421gln (accessed [today's date]).

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