Is SAG p.Pro12= (c.36G>A) pathogenic?

SAG p.Pro12= (c.36G>A) is classified Conflicting classifications of pathogenicity in SAG (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-24). Very rare (popmax 0.000593%, nfe); Associated with inherited retinal dystrophy.

What condition is associated with SAG p.Pro12= (c.36G>A)?

SAG p.Pro12= (c.36G>A) is associated with inherited retinal dystrophy (ClinVar).

How common is SAG p.Pro12= (c.36G>A) in the general population?

SAG p.Pro12= (c.36G>A) is very rare (popmax 0.000593%, nfe) (gnomAD).

SAG p.Pro12=

c.36G>A · rs765255437 · VCV1924889

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.44	GERP -2.7
Overall
CADD	4.476	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000593% European (non-Finnish) · 7/1,179,804 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000558% 9/1,613,686 alleles · very rare exomes 7/1,461,480 · genomes 2/152,206 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,456
Finnishnot grpmax-eligible	0.00156%	64,000
European (non-Finnish)grpmax	0.000593%	168,543

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro12=
Coding: c.36G>A
MANE Select: NM_000541
dbSNP: rs765255437
Type: single nucleotide variant
Location: chr2:233309225 (GRCh38)
Structure: AlphaFold pLDDT 83.02 · 7 PDB
Residue 12: the 'disordered' region

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

RNF7 p.Ala12Thr Uncertain significance ★ ⚠ same residue
SAG p.Pro12Leu Conflicting classifications of pathogenicity ★ ⚠ 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-pro12 (accessed [today's date]).

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