Is SAG p.Pro127Ser (c.379C>T) pathogenic?

SAG p.Pro127Ser (c.379C>T) is classified Uncertain significance in SAG (ClinVar, No assertion criteria, 1 submitter; last evaluated 2017-01-01). AlphaMissense: ambiguous (0.5406); Very rare (popmax 0.000174%, nfe); Associated with inherited retinal dystrophy.

What condition is associated with SAG p.Pro127Ser (c.379C>T)?

SAG p.Pro127Ser (c.379C>T) is associated with inherited retinal dystrophy (ClinVar).

How common is SAG p.Pro127Ser (c.379C>T) in the general population?

SAG p.Pro127Ser (c.379C>T) is very rare (popmax 0.000174%, nfe) (gnomAD).

What do computational predictors say about SAG p.Pro127Ser (c.379C>T)?

AlphaMissense predicts ambiguous (score 0.5406) — an in-silico prediction, not a clinical call.

SAG p.Pro127Ser

c.379C>T · VCV3250199

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5406 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000174%, nfe)

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.5406	ambiguous
REVEL	0.434	indeterminate
SaProt	LLR -10.77	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Overall
CADD	28.1	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 0.000174% European (non-Finnish) · 2/1,147,662 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000128% 2/1,562,020 alleles · very rare exomes 2/1,409,726 · genomes 0/152,294 · 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: SAG
Protein: p.Pro127Ser
Coding: c.379C>T
MANE Select: NM_000541
Type: single nucleotide variant
Location: chr2:233322949 (GRCh38)
Structure: AlphaFold pLDDT 83.02 · 7 PDB

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

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SAG p.Pro127Arg Uncertain significance ★★ ⚠ same residue
SAG p.Pro127= Likely benign ★ same residue
SAG p.Arg193Ter Pathogenic ★★ same condition
SAG p.Ala101Val Uncertain significance ★★ ⚠ same condition
SAG p.Arg322Gln Uncertain significance ★★ ⚠ same condition
SAG p.Arg358His Uncertain significance ★★ ⚠ same condition
SAG p.Phe379Ser Uncertain significance ★★ ⚠ same condition
SAG p.Ser146Tyr 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/sag-p-pro127ser (accessed [today's date]).

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