Is SMO p.Pro705Ser (c.2113C>T) pathogenic?

SMO p.Pro705Ser (c.2113C>T) is classified Uncertain significance in SMO (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-16). AlphaMissense: ambiguous (0.5393); Ultra-rare (popmax 0.0335%, mid); Associated with Inborn genetic diseases.

What condition is associated with SMO p.Pro705Ser (c.2113C>T)?

SMO p.Pro705Ser (c.2113C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SMO p.Pro705Ser (c.2113C>T) in the general population?

SMO p.Pro705Ser (c.2113C>T) is ultra-rare (popmax 0.0335%, mid) (gnomAD).

What do computational predictors say about SMO p.Pro705Ser (c.2113C>T)?

AlphaMissense predicts ambiguous (score 0.5393) — an in-silico prediction, not a clinical call.

SMO p.Pro705Ser

c.2113C>T · VCV4170636

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5393 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0335%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5393	ambiguous
REVEL	0.458	indeterminate
SaProt	LLR -7.03	tolerated
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	25.3	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 0.0335% Middle Eastern · 2/5,964 alleles

Filtering AF 0.00591% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00245%

Overall 0.00032% 5/1,564,744 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0335%	2,982
Remaining individualsnot grpmax-eligible	0.00495%	20,194

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.Pro705Ser
Coding: c.2113C>T
MANE Select: NM_005631
Type: single nucleotide variant
Location: chr7:129212200 (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-pro705ser (accessed [today's date]).

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