Is IMPG1 p.Pro396Ser (c.1186C>T) pathogenic?

IMPG1 p.Pro396Ser (c.1186C>T) is classified Uncertain significance in IMPG1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-17). AlphaMissense: likely benign (0.0919); Very rare (popmax 0.00263%, nfe).

How common is IMPG1 p.Pro396Ser (c.1186C>T) in the general population?

IMPG1 p.Pro396Ser (c.1186C>T) is very rare (popmax 0.00263%, nfe) (gnomAD).

What do computational predictors say about IMPG1 p.Pro396Ser (c.1186C>T)?

AlphaMissense predicts likely benign (score 0.0919) — an in-silico prediction, not a clinical call.

IMPG1 p.Pro396Ser

c.1186C>T · rs371337067 · VCV1035706

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0919 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00263%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0919	likely benign
REVEL	0.022	moderately benign-leaning
SaProt	LLR -5.95	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 2.1	GERP -1.5, phastCons 0.45
Regional constraint	o/e 1.17	unconstrained · MANE · 122 kb · p 5.6e-05 · regional, not allelic
Overall
CADD	16.42	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 0.00263% European (non-Finnish) · 31/1,179,614 alleles

Filtering AF 0.00188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.00192% 31/1,613,036 alleles · very rare exomes 30/1,460,870 · genomes 1/152,166 · 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.Pro396Ser
Coding: c.1186C>T
MANE Select: NM_001563
dbSNP: rs371337067
Type: single nucleotide variant
Location: chr6:76003900 (GRCh38)
Gene constraint: LOEUF 1.217 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.26

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

Similar variants

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
IMPG1 p.Arg507Ter Pathogenic/Likely pathogenic ★★ same type
IMPG1 p.Arg571Ter 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-pro396ser (accessed [today's date]).

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