Is SAG p.Pro364Ser (c.1090C>T) pathogenic?

SAG p.Pro364Ser (c.1090C>T) is classified Uncertain significance in SAG (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-04). AlphaMissense: likely benign (0.1176); Ultra-rare (popmax 0.033%, mid).

How common is SAG p.Pro364Ser (c.1090C>T) in the general population?

SAG p.Pro364Ser (c.1090C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about SAG p.Pro364Ser (c.1090C>T)?

AlphaMissense predicts likely benign (score 0.1176) — an in-silico prediction, not a clinical call.

SAG p.Pro364Ser

c.1090C>T · rs896291630 · VCV2968883

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1176 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1176	likely benign
REVEL	0.25	benign-leaning
SaProt	LLR -9.21	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 5.9	GERP 1.4, phastCons 1
Overall
CADD	25.9	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 0.033% Middle Eastern · 2/6,058 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.000373% 6/1,607,802 alleles · ultra-rare exomes 6/1,455,552 · genomes 0/152,250 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,029
Remaining individualsnot grpmax-eligible	0.00161%	62,298
South Asian	0.00111%	89,828
European (non-Finnish)	0.00017%	588,311

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: SAG
Protein: p.Pro364Ser
Coding: c.1090C>T
MANE Select: NM_000541
dbSNP: rs896291630
Type: single nucleotide variant
Location: chr2:233342314 (GRCh38)
Structure: AlphaFold pLDDT 83.02 · 7 PDB

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

Similar variants

SAG p.Pro364Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
SAG c.1023-2A>G Likely pathogenic ★★ same type
SAG c.1103-2A>C Pathogenic/Likely pathogenic ★★ same type
SAG c.136+2T>C Likely pathogenic ★★ same type
SAG c.136+2T>G Pathogenic/Likely pathogenic ★★ same type
SAG c.181+1G>A Likely pathogenic ★★ same type
SAG c.182-2A>G Pathogenic/Likely pathogenic ★★ same type
SAG c.376-2A>G Pathogenic/Likely pathogenic ★★ 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/sag-p-pro364ser (accessed [today's date]).

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