Is IMPG2 p.Pro409Leu (c.1226C>T) pathogenic?

IMPG2 p.Pro409Leu (c.1226C>T) is classified Uncertain significance in IMPG2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-17). AlphaMissense: likely benign (0.0821); Very rare (popmax 0.00331%, sas); Associated with Inborn genetic diseases.

What condition is associated with IMPG2 p.Pro409Leu (c.1226C>T)?

IMPG2 p.Pro409Leu (c.1226C>T) is associated with Inborn genetic diseases (ClinVar).

How common is IMPG2 p.Pro409Leu (c.1226C>T) in the general population?

IMPG2 p.Pro409Leu (c.1226C>T) is very rare (popmax 0.00331%, sas) (gnomAD).

What do computational predictors say about IMPG2 p.Pro409Leu (c.1226C>T)?

AlphaMissense predicts likely benign (score 0.0821) — an in-silico prediction, not a clinical call.

IMPG2 p.Pro409Leu

c.1226C>T · rs777952275 · VCV1926446

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0821 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00331%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0821	likely benign
REVEL	0.029	moderately benign-leaning
SaProt	LLR -6.47	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.2	GERP -1.9
Regional constraint	o/e 0.98	unconstrained · MANE · 93 kb · p 0.41 · regional, not allelic
Overall
CADD	12.42	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 0.00331% South Asian · 3/90,738 alleles

Filtering AF 0.000879% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000719%

Overall 0.00137% 22/1,610,630 alleles · very rare exomes 19/1,458,552 · genomes 3/152,078 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00331%	30,246
Remaining individualsnot grpmax-eligible	0.0016%	62,336
European (non-Finnish)	0.00144%	69,291
African / African-American	0.00134%	74,804

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.Pro409Leu
Coding: c.1226C>T
MANE Select: NM_016247
dbSNP: rs777952275
Type: single nucleotide variant
Location: chr3:101253709 (GRCh38)
Gene constraint: LOEUF 0.773 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.28
Residue 409: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

IMPG2 p.Pro409Ala Uncertain significance ★★ ⚠ same residue
IMPG2 p.Pro409= Benign/Likely benign ★★ same residue
IMPG2 p.Ala1230Ser Uncertain significance ★★ ⚠ same condition
IMPG2 p.Ala1231Val Uncertain significance ★★ ⚠ same condition
IMPG2 p.Ala207Thr Uncertain significance ★★ ⚠ same condition
IMPG2 p.Ala280Ser Uncertain significance ★★ ⚠ same condition
IMPG2 p.Ala419Asp Uncertain significance ★★ ⚠ same condition
IMPG2 p.Ala741Asp Uncertain significance ★★ ⚠ 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-pro409leu (accessed [today's date]).

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