Is IMPG2 p.Leu1127= (c.3381C>T) pathogenic?

IMPG2 p.Leu1127= (c.3381C>T) is classified Benign in IMPG2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Common (popmax 82.5%, amr) — too common for a highly-penetrant pathogenic allele; Associated with inherited retinal dystrophy.

What condition is associated with IMPG2 p.Leu1127= (c.3381C>T)?

IMPG2 p.Leu1127= (c.3381C>T) is associated with inherited retinal dystrophy, retinitis pigmentosa 56, vitelliform macular dystrophy 5 (ClinVar).

IMPG2 p.Leu1127=

Q: How common is IMPG2 p.Leu1127= (c.3381C>T) in the general population?

IMPG2 p.Leu1127= (c.3381C>T) is common (popmax 82.5%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3381C>T · rs348867 · VCV342337

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 82.5%, amr) — too common for a highly-penetrant pathogenic allele

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 3.8	GERP 0.17, phastCons 1
Overall
CADD	1.203	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 82.5% Admixed American · 49,506/60,014 alleles

Filtering AF 81.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 81.6%

Overall 78.7% 1,269,309/1,613,038 alleles · common exomes 1,147,492/1,460,918 · genomes 121,817/152,120 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	88.6%	1
Finnishnot grpmax-eligible	83.7%	1
Admixed Americangrpmax	82.5%	1
African / African-American	82.1%	1
European (non-Finnish)	78.7%	1
East Asian	78.1%	1
Remaining individualsnot grpmax-eligible	77.6%	1
South Asian	74.9%	1
Middle Eastern	70.6%	1
Ashkenazi Jewishnot grpmax-eligible	68.4%	1

Amish 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.Leu1127=
Coding: c.3381C>T
MANE Select: NM_016247
dbSNP: rs348867
Type: single nucleotide variant
Location: chr3:101230998 (GRCh38)
Gene constraint: LOEUF 0.773 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.28
Residue 1127: the 'hyaluronan-binding motif involved in chondroitin sulfate a- and c-binding' region; 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

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

Also linked: retinitis pigmentosa 56 vitelliform macular dystrophy 5 retinitis pigmentosa

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-leu1127 (accessed [today's date]).

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