Is IMPG1 p.Pro646Ala (c.1936C>G) pathogenic?

IMPG1 p.Pro646Ala (c.1936C>G) is classified Uncertain significance in IMPG1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-24). AlphaMissense: likely benign (0.2465); Very rare (popmax 0.000763%, nfe).

How common is IMPG1 p.Pro646Ala (c.1936C>G) in the general population?

IMPG1 p.Pro646Ala (c.1936C>G) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about IMPG1 p.Pro646Ala (c.1936C>G)?

AlphaMissense predicts likely benign (score 0.2465) — an in-silico prediction, not a clinical call.

IMPG1 p.Pro646Ala

c.1936C>G · rs761616758 · VCV965688

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2465 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2465	likely benign
REVEL	0.352	indeterminate
SaProt	LLR -8.54	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 29 kb · p 0.44 · regional, not allelic
Overall
CADD	24.3	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 0.000763% European (non-Finnish) · 9/1,179,718 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,613,668 alleles · very rare exomes 9/1,461,482 · genomes 0/152,186 · 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: IMPG1
Protein: p.Pro646Ala
Coding: c.1936C>G
MANE Select: NM_001563
dbSNP: rs761616758
Type: single nucleotide variant
Location: chr6:75947422 (GRCh38)
Gene constraint: LOEUF 1.217 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.26
Residue 646: the sea 2 domain

Full IMPG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IMPG1 p.Pro646= Benign/Likely benign ★★ same residue
IMPG1 p.Pro646Leu Uncertain significance ★ same residue
IMPG1 c.1212+2T>C Likely pathogenic ★★ same type
IMPG1 c.1291+1G>T Pathogenic/Likely pathogenic ★★ same type
IMPG1 c.1824+1G>A Pathogenic/Likely pathogenic ★★ same type
IMPG1 c.498-1G>C Likely pathogenic ★★ same type
IMPG1 c.807+1G>A Pathogenic/Likely pathogenic ★★ same type
IMPG1 c.807+2T>A 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/impg1-p-pro646ala (accessed [today's date]).

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