Is GRIP1 p.Pro596Ser (c.1786C>T) pathogenic?

GRIP1 p.Pro596Ser (c.1786C>T) is classified Uncertain significance in GRIP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-17). AlphaMissense: likely benign (0.1197); Very rare (popmax 0.00175%, nfe); Associated with Fraser syndrome 3.

What condition is associated with GRIP1 p.Pro596Ser (c.1786C>T)?

GRIP1 p.Pro596Ser (c.1786C>T) is associated with Fraser syndrome 3 (ClinVar).

How common is GRIP1 p.Pro596Ser (c.1786C>T) in the general population?

GRIP1 p.Pro596Ser (c.1786C>T) is very rare (popmax 0.00175%, nfe) (gnomAD).

What do computational predictors say about GRIP1 p.Pro596Ser (c.1786C>T)?

AlphaMissense predicts likely benign (score 0.1197) — an in-silico prediction, not a clinical call.

GRIP1 p.Pro596Ser

c.1786C>T · VCV3575199

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1197 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00175%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Fraser syndrome 3

Computational evidence

Protein change
AlphaMissense	0.1197	likely benign
REVEL	0.43	indeterminate
SaProt	LLR -7.21	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Overall
CADD	26.5	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 0.00175% European (non-Finnish) · 20/1,144,478 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000928%

Overall 0.00127% 20/1,575,122 alleles · very rare exomes 16/1,423,044 · genomes 4/152,078 · 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: GRIP1
Protein: p.Pro596Ser
Coding: c.1786C>T
MANE Select: NM_001366722
Type: single nucleotide variant
Location: chr12:66420772 (GRCh38)
Structure: AlphaFold pLDDT 89.07

Full GRIP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Fraser syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GRIP1 p.Pro596Arg Benign/Likely benign ★★ same residue
GRIP1 p.Cys10Ter Pathogenic/Likely pathogenic ★★ same condition
GRIP1 c.55+3A>C Uncertain significance ★★ same condition
GRIP1 c.-172A>G Uncertain significance ★★ same condition
GRIP1 c.*99G>A Uncertain significance ★★ same condition
GRIP1 p.Ala170Thr Uncertain significance ★★ ⚠ same condition
GRIP1 p.Ala261Thr Uncertain significance ★★ ⚠ same condition
GRIP1 p.Ala36Val 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/grip1-p-pro596ser (accessed [today's date]).

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