Is IMPG2 p.Thr751Ala (c.2251A>G) pathogenic?

IMPG2 p.Thr751Ala (c.2251A>G) is classified Uncertain significance in IMPG2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-02-01). AlphaMissense: likely benign (0.075); Very rare (popmax 0.00432%, nfe).

How common is IMPG2 p.Thr751Ala (c.2251A>G) in the general population?

IMPG2 p.Thr751Ala (c.2251A>G) is very rare (popmax 0.00432%, nfe) (gnomAD).

What do computational predictors say about IMPG2 p.Thr751Ala (c.2251A>G)?

AlphaMissense predicts likely benign (score 0.075) — an in-silico prediction, not a clinical call.

IMPG2 p.Thr751Ala

c.2251A>G · rs371240065 · VCV1484251

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.075 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00432%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.075	likely benign
REVEL	0.01	strongly benign-leaning
SaProt	LLR -7.38	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 0.1	GERP -5.2, phastCons 0.066
Regional constraint	o/e 0.98	unconstrained · MANE · 93 kb · p 0.41 · regional, not allelic
Overall
CADD	6.008	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 0.00432% European (non-Finnish) · 51/1,180,040 alleles

Filtering AF 0.00334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00302%

Overall 0.00328% 53/1,613,920 alleles · very rare exomes 51/1,461,680 · genomes 2/152,240 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00432%	23,138
Remaining individualsnot grpmax-eligible	0.0016%	62,486
Finnishnot grpmax-eligible	0.00157%	63,848

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.Thr751Ala
Coding: c.2251A>G
MANE Select: NM_016247
dbSNP: rs371240065
Type: single nucleotide variant
Location: chr3:101244080 (GRCh38)
Gene constraint: LOEUF 0.773 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.28
Residue 751: 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

Similar variants

IMPG2 c.1240-1G>A Likely pathogenic ★★ same type
IMPG2 c.1240-2A>G Pathogenic/Likely pathogenic ★★ same type
IMPG2 c.502-2A>G Likely pathogenic ★★ same type
IMPG2 c.583+1G>C Pathogenic/Likely pathogenic ★★ same type
IMPG2 c.667-1G>A Pathogenic/Likely pathogenic ★★ same type
IMPG2 c.828+1G>A Pathogenic/Likely pathogenic ★★ same type
IMPG2 c.829-1G>T Pathogenic/Likely pathogenic ★★ same type
IMPG2 c.829-2A>T Pathogenic/Likely pathogenic ★★ same type

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-thr751ala (accessed [today's date]).

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