Is GRIP1 p.Pro596Arg (c.1787C>G) pathogenic?

GRIP1 p.Pro596Arg (c.1787C>G) is classified Benign/Likely benign in GRIP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-21). AlphaMissense: likely benign (0.2837); Rare (popmax 0.709%, sas); Associated with Fraser syndrome 3.

What condition is associated with GRIP1 p.Pro596Arg (c.1787C>G)?

GRIP1 p.Pro596Arg (c.1787C>G) is associated with Fraser syndrome 3 (ClinVar).

How common is GRIP1 p.Pro596Arg (c.1787C>G) in the general population?

GRIP1 p.Pro596Arg (c.1787C>G) is rare (popmax 0.709%, sas) (gnomAD).

What do computational predictors say about GRIP1 p.Pro596Arg (c.1787C>G)?

AlphaMissense predicts likely benign (score 0.2837) — an in-silico prediction, not a clinical call.

GRIP1 p.Pro596Arg

c.1787C>G · rs200955760 · VCV310306

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2837 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.709%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Fraser syndrome 3

Computational evidence

Protein change
AlphaMissense	0.2837	likely benign
REVEL	0.642	indeterminate
SaProt	LLR -7.93	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 9.8	GERP 1.9, phastCons 1
Overall
CADD	26.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.709% South Asian · 640/90,320 alleles

Filtering AF 0.663% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.645%

Overall 0.0444% 700/1,578,244 alleles · rare exomes 670/1,426,018 · genomes 30/152,226 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.709%	141
Middle Eastern	0.0501%	1,995
Remaining individualsnot grpmax-eligible	0.0326%	3,066
European (non-Finnish)	0.00305%	32,779
East Asian	0.00224%	44,668
African / African-American	0.00134%	74,426

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.Pro596Arg
Coding: c.1787C>G
MANE Select: NM_001366722
dbSNP: rs200955760
Type: single nucleotide variant
Location: chr12:66420771 (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.Pro596Ser Uncertain significance ★ ⚠ 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-pro596arg (accessed [today's date]).

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