Is IMPG2 p.Pro434Ser (c.1300C>T) pathogenic?

IMPG2 p.Pro434Ser (c.1300C>T) is classified Uncertain significance in IMPG2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-14). AlphaMissense: likely benign (0.0753); Rare (popmax 0.198%, mid); Associated with retinitis pigmentosa 56.

What condition is associated with IMPG2 p.Pro434Ser (c.1300C>T)?

IMPG2 p.Pro434Ser (c.1300C>T) is associated with retinitis pigmentosa 56, vitelliform macular dystrophy 5 (ClinVar).

How common is IMPG2 p.Pro434Ser (c.1300C>T) in the general population?

IMPG2 p.Pro434Ser (c.1300C>T) is rare (popmax 0.198%, mid) (gnomAD).

How is Retinitis pigmentosa inherited?

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

What do computational predictors say about IMPG2 p.Pro434Ser (c.1300C>T)?

AlphaMissense predicts likely benign (score 0.0753) — an in-silico prediction, not a clinical call.

IMPG2 p.Pro434Ser

c.1300C>T · rs201924170 · VCV853888

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0753 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.198%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

retinitis pigmentosa 56

Computational evidence

Protein change
AlphaMissense	0.0753	likely benign
REVEL	0.114	moderately benign-leaning
SaProt	LLR -5.14	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 3.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 93 kb · p 0.41 · regional, not allelic
Overall
CADD	19.2	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 0.198% Middle Eastern · 12/6,060 alleles

Filtering AF 0.114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0895%

Overall 0.012% 193/1,614,124 alleles · rare exomes 170/1,461,826 · genomes 23/152,298 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.198%	505
Remaining individualsnot grpmax-eligible	0.0448%	2,233
Finnishnot grpmax-eligible	0.0422%	2,372
Admixed American	0.0233%	4,286
European (non-Finnish)	0.00932%	10,727
South Asian	0.0022%	45,541

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.Pro434Ser
Coding: c.1300C>T
MANE Select: NM_016247
dbSNP: rs201924170
Type: single nucleotide variant
Location: chr3:101246045 (GRCh38)
Gene constraint: LOEUF 0.773 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.28
Residue 434: a UniProt-annotated variant site (in rp56); a UniProt-annotated variant site (in vmd5)

Full IMPG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

retinitis pigmentosa 56 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: vitelliform macular dystrophy 5

For Retinitis pigmentosa (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

IMPG2 c.1240-2A>G Pathogenic/Likely pathogenic ★★ same condition
IMPG2 c.583+1G>C Pathogenic/Likely pathogenic ★★ same condition
IMPG2 c.667-1G>A Pathogenic/Likely pathogenic ★★ same condition
IMPG2 c.828+1G>A Pathogenic/Likely pathogenic ★★ same condition
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

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-pro434ser (accessed [today's date]).

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