Is SGMS2 p.Pro65Arg (c.194C>G) pathogenic?

SGMS2 p.Pro65Arg (c.194C>G) is classified Uncertain significance in SGMS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-16). AlphaMissense: ambiguous (0.3463); Very rare (popmax 0.00347%, nfe).

How common is SGMS2 p.Pro65Arg (c.194C>G) in the general population?

SGMS2 p.Pro65Arg (c.194C>G) is very rare (popmax 0.00347%, nfe) (gnomAD).

What do computational predictors say about SGMS2 p.Pro65Arg (c.194C>G)?

AlphaMissense predicts ambiguous (score 0.3463) — an in-silico prediction, not a clinical call.

SGMS2 p.Pro65Arg

c.194C>G · VCV3674160

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3463 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00347%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.3463	ambiguous
REVEL	0.263	benign-leaning
SaProt	LLR -7.91	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.6	GERP 2.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 15 kb · p 0.0049 · regional, not allelic
Overall
CADD	24.9	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 0.00347% European (non-Finnish) · 41/1,179,952 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00233%

Overall 0.00254% 41/1,613,784 alleles · very rare exomes 40/1,461,660 · genomes 1/152,124 · joint denominator

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.Pro65Arg
Coding: c.194C>G
MANE Select: NM_001375905
Type: single nucleotide variant
Location: chr4:107895747 (GRCh38)

Full SGMS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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-pro65arg (accessed [today's date]).

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