Is IMPG2 p.Ser319Arg (c.957C>A) pathogenic?

IMPG2 p.Ser319Arg (c.957C>A) is classified Uncertain significance in IMPG2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-08-06). AlphaMissense: likely pathogenic (0.7604); Very rare (popmax 0.00334%, amr); Associated with inherited retinal dystrophy.

What condition is associated with IMPG2 p.Ser319Arg (c.957C>A)?

IMPG2 p.Ser319Arg (c.957C>A) is associated with inherited retinal dystrophy (ClinVar).

How common is IMPG2 p.Ser319Arg (c.957C>A) in the general population?

IMPG2 p.Ser319Arg (c.957C>A) is very rare (popmax 0.00334%, amr) (gnomAD).

What do computational predictors say about IMPG2 p.Ser319Arg (c.957C>A)?

AlphaMissense predicts likely pathogenic (score 0.7604) — an in-silico prediction, not a clinical call.

IMPG2 p.Ser319Arg

c.957C>A · rs752527328 · VCV1928527

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7604 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.7604	likely pathogenic · top 9% in IMPG2
REVEL	0.209	benign-leaning
SaProt	LLR -6.85	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.7	GERP -0.17, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 93 kb · p 0.41 · regional, not allelic
Overall
CADD	22.9	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 0.00334% Admixed American · 2/59,870 alleles

Filtering AF 0.000554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.00062% 10/1,613,076 alleles · very rare exomes 7/1,460,958 · genomes 3/152,118 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00641%	15,611
Admixed Americangrpmax	0.00334%	29,935
European (non-Finnish)	0.000339%	294,839

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: IMPG2
Protein: p.Ser319Arg
Coding: c.957C>A
MANE Select: NM_016247
dbSNP: rs752527328
Type: single nucleotide variant
Location: chr3:101257725 (GRCh38)
Gene constraint: LOEUF 0.773 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.28
Residue 319: a UniProt-annotated variant site (in rp56); a UniProt-annotated variant site (in vmd5); the sea 1 domain

Full IMPG2 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

IMPG2 p.Arg1088Ter Pathogenic/Likely pathogenic ★★ same condition
IMPG2 p.Arg906Ter Pathogenic ★★ same condition
IMPG2 p.Arg964Ter Pathogenic ★★ same condition
IMPG2 p.Gln363Ter Pathogenic ★★ same condition
IMPG2 p.Gln814Ter Pathogenic/Likely pathogenic ★★ same condition
IMPG2 p.Gln856Ter Pathogenic ★★ same condition
IMPG2 p.Glu1164Ter Pathogenic/Likely pathogenic ★★ same condition
IMPG2 p.Glu226Ter Pathogenic/Likely pathogenic ★★ 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/impg2-p-ser319arg (accessed [today's date]).

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