Is IMPG2 p.Phe1016Ser (c.3047T>C) pathogenic?

IMPG2 p.Phe1016Ser (c.3047T>C) is classified Likely pathogenic in IMPG2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-10-27). AlphaMissense: likely pathogenic (0.9925); Very rare (popmax 8.47e-05%, nfe); Associated with IMPG2-related disorders.

What condition is associated with IMPG2 p.Phe1016Ser (c.3047T>C)?

IMPG2 p.Phe1016Ser (c.3047T>C) is associated with IMPG2-related disorders, vitelliform macular dystrophy 5, inherited retinal dystrophy (ClinVar).

How common is IMPG2 p.Phe1016Ser (c.3047T>C) in the general population?

IMPG2 p.Phe1016Ser (c.3047T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about IMPG2 p.Phe1016Ser (c.3047T>C)?

AlphaMissense predicts likely pathogenic (score 0.9925) — an in-silico prediction, not a clinical call.

IMPG2 p.Phe1016Ser

c.3047T>C · rs2508925531 · VCV2627610

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9925 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

IMPG2-related disorders

Computational evidence

Protein change
AlphaMissense	0.9925	likely pathogenic ✓ concordant with ClinVar · top 1% in IMPG2
REVEL	0.536	indeterminate
SaProt	LLR -14.54	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 93 kb · p 0.41 · regional, not allelic
Overall
CADD	25.5	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 8.47e-05% European (non-Finnish) · 1/1,179,986 alleles

Overall 6.2e-05% 1/1,614,072 alleles · very rare exomes 1/1,461,816 · genomes 0/152,256 · 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: IMPG2
Protein: p.Phe1016Ser
Coding: c.3047T>C
MANE Select: NM_016247
dbSNP: rs2508925531
Type: single nucleotide variant
Location: chr3:101232967 (GRCh38)
Gene constraint: LOEUF 0.773 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.28
Residue 1016: a UniProt-annotated variant site (in rp56); a UniProt-annotated variant site (in vmd5); a UniProt-annotated variant site (found in a patient with vmd5; uncertain significance); the egf-like 1 domain

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

Disease context

IMPG2-related disorders

Also linked: vitelliform macular dystrophy 5 inherited retinal dystrophy

Similar variants

IMPG2 c.1240-1G>A Likely pathogenic ★★ same condition
IMPG2 c.1240-2A>G Pathogenic/Likely pathogenic ★★ same condition
IMPG2 c.502-2A>G Likely pathogenic ★★ same condition
IMPG2 c.667-1G>A Pathogenic/Likely pathogenic ★★ same condition
IMPG2 c.829-1G>T Pathogenic/Likely pathogenic ★★ same condition
IMPG2 p.Arg1088Ter Pathogenic/Likely pathogenic ★★ same condition
IMPG2 p.Arg127Ter Pathogenic ★★ same condition
IMPG2 p.Arg906Ter 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-phe1016ser (accessed [today's date]).

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