Is CRB1 p.Arg1373Ser (c.4119G>T) pathogenic?

CRB1 p.Arg1373Ser (c.4119G>T) is classified Uncertain significance in CRB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: likely pathogenic (0.6471); Very rare (popmax 6.84e-05%); Associated with Inborn genetic diseases.

What condition is associated with CRB1 p.Arg1373Ser (c.4119G>T)?

CRB1 p.Arg1373Ser (c.4119G>T) is associated with Inborn genetic diseases (ClinVar).

How common is CRB1 p.Arg1373Ser (c.4119G>T) in the general population?

CRB1 p.Arg1373Ser (c.4119G>T) is very rare (popmax 6.84e-05%) (gnomAD).

What do computational predictors say about CRB1 p.Arg1373Ser (c.4119G>T)?

AlphaMissense predicts likely pathogenic (score 0.6471) — an in-silico prediction, not a clinical call.

CRB1 p.Arg1373Ser

c.4119G>T · VCV4006670

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6471 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6471	likely pathogenic
REVEL	0.661	pathogenic-leaning
SaProt	LLR -8.64	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.53	GERP 0.012, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 209 kb · p 0.78 · regional, not allelic
Overall
CADD	21.2	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 6.84e-05%

Overall 6.84e-05% 1/1,461,662 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.Arg1373Ser
Coding: c.4119G>T
MANE Select: NM_201253
Type: single nucleotide variant
Location: chr1:197477777 (GRCh38)
Gene constraint: LOEUF 0.776 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.19 · 1 PDB
Residue 1373: a UniProt-annotated variant site (in lca8); the 'interaction with epb41l5' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CRB1 p.Arg1373Lys Uncertain significance ★ same residue
CRB1 p.Arg1373= Likely benign ★ same residue
CRB1 p.Ala921Val Uncertain significance ★★ ⚠ same condition
CRB1 p.Arg1286Trp Uncertain significance ★★ ⚠ same condition
CRB1 p.Arg1383Cys Uncertain significance ★★ ⚠ same condition
CRB1 p.Arg1383Leu Uncertain significance ★★ ⚠ same condition
CRB1 p.Arg905Trp Uncertain significance ★★ ⚠ same condition
CRB1 p.Asn1243His 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/crb1-p-arg1373ser (accessed [today's date]).

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