Is SAG p.Ser25= (c.75G>A) pathogenic?

SAG p.Ser25= (c.75G>A) is classified Conflicting classifications of pathogenicity in SAG (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-06-21). Very rare (popmax 0.00223%, eas); Associated with cone dystrophy.

What condition is associated with SAG p.Ser25= (c.75G>A)?

SAG p.Ser25= (c.75G>A) is associated with cone dystrophy (ClinVar).

How common is SAG p.Ser25= (c.75G>A) in the general population?

SAG p.Ser25= (c.75G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Progressive cone dystrophy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

SAG p.Ser25=

c.75G>A · rs1484802068 · VCV813236

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

cone dystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.56	donor loss · deltas
Pangolin	Δ0.53	gain · loss 0.46 · SpliceAI calls loss · independent
Constraint at this position
Conservation	phyloP 0.95	GERP -0.36, phastCons 1
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,830 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,611,814 alleles · very rare exomes 4/1,459,576 · genomes 0/152,238 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,830
European (non-Finnish)	0.000255%	392,714

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.Ser25=
Coding: c.75G>A
MANE Select: NM_000541
dbSNP: rs1484802068
Type: single nucleotide variant
Location: chr2:233309264 (GRCh38)
Structure: AlphaFold pLDDT 83.02 · 7 PDB
Residue 25: the 'disordered' region

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

Disease context

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

For Progressive cone dystrophy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adult

Similar variants

SAG p.Ser25Leu Uncertain significance ★★ ⚠ same residue
SAG p.Ser25Ter Pathogenic ★ 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

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-ser25 (accessed [today's date]).

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