Is CRB1 p.Pro777Ser (c.2329C>T) pathogenic?

CRB1 p.Pro777Ser (c.2329C>T) is classified Uncertain significance in CRB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-30). AlphaMissense: likely benign (0.1005); Very rare (popmax 8.47e-05%, nfe).

How common is CRB1 p.Pro777Ser (c.2329C>T) in the general population?

CRB1 p.Pro777Ser (c.2329C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CRB1 p.Pro777Ser (c.2329C>T)?

AlphaMissense predicts likely benign (score 0.1005) — an in-silico prediction, not a clinical call.

CRB1 p.Pro777Ser

c.2329C>T · VCV4926736

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1005 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1005	likely benign
REVEL	0.379	indeterminate
SaProt	LLR -3.56	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP -0.44, phastCons 0.95
Regional constraint	o/e 1.01	unconstrained · MANE · 209 kb · p 0.78 · regional, not allelic
Overall
CADD	7.58	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 8.47e-05% European (non-Finnish) · 1/1,179,952 alleles

Overall 6.84e-05% 1/1,461,668 alleles · very rare

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: CRB1
Protein: p.Pro777Ser
Coding: c.2329C>T
MANE Select: NM_201253
Type: single nucleotide variant
Location: chr1:197427654 (GRCh38)
Gene constraint: LOEUF 0.776 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.19 · 1 PDB
Residue 777: a UniProt-annotated variant site (in lca8); the laminin g-like 2 domain

Full CRB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CRB1 p.Pro777Leu Uncertain significance ★★ ⚠ same residue
CRB1 p.Pro777Ala Uncertain significance ★ ⚠ same residue
CRB1 p.Pro777fs Likely pathogenic ★ same residue
CRB1 c.1172-2A>G Likely pathogenic ★★ same type
CRB1 c.2128+1G>C Pathogenic/Likely pathogenic ★★ same type
CRB1 c.2129-1G>A Pathogenic/Likely pathogenic ★★ same type
CRB1 c.2129-1G>C Pathogenic ★★ same type
CRB1 c.2129-2A>G 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/crb1-p-pro777ser (accessed [today's date]).

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