Is SGMS2 p.Pro65Ser (c.193C>T) pathogenic?

SGMS2 p.Pro65Ser (c.193C>T) is classified Uncertain significance in SGMS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-31). AlphaMissense: likely benign (0.2605); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with SGMS2 p.Pro65Ser (c.193C>T)?

SGMS2 p.Pro65Ser (c.193C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SGMS2 p.Pro65Ser (c.193C>T) in the general population?

SGMS2 p.Pro65Ser (c.193C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about SGMS2 p.Pro65Ser (c.193C>T)?

AlphaMissense predicts likely benign (score 0.2605) — an in-silico prediction, not a clinical call.

SGMS2 p.Pro65Ser

c.193C>T · VCV3440603

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2605 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2605	likely benign
REVEL	0.133	moderately benign-leaning
SaProt	LLR -6.30	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 15 kb · p 0.0049 · regional, not allelic
Overall
CADD	19.49	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

Grpmax group 0.00167% Admixed American · 1/59,950 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,910 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,950
European (non-Finnish)	0.000169%	589,977

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: SGMS2
Protein: p.Pro65Ser
Coding: c.193C>T
Type: single nucleotide variant
Location: chr4:107895746 (GRCh38)

Full SGMS2 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

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/sgms2-p-pro65ser (accessed [today's date]).

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