Is CRB2 p.Leu1237Ile (c.3709C>A) pathogenic?

CRB2 p.Leu1237Ile (c.3709C>A) is classified Uncertain significance in CRB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-13). AlphaMissense: likely benign (0.1859); Ultra-rare (popmax 0.0165%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CRB2 p.Leu1237Ile (c.3709C>A)?

CRB2 p.Leu1237Ile (c.3709C>A) is associated with Inborn genetic diseases (ClinVar).

How common is CRB2 p.Leu1237Ile (c.3709C>A) in the general population?

CRB2 p.Leu1237Ile (c.3709C>A) is ultra-rare (popmax 0.0165%, nfe) (gnomAD).

What do computational predictors say about CRB2 p.Leu1237Ile (c.3709C>A)?

AlphaMissense predicts likely benign (score 0.1859) — an in-silico prediction, not a clinical call.

CRB2 p.Leu1237Ile

c.3709C>A · rs373603388 · VCV2391015

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1859 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1859	likely benign
REVEL	0.388	indeterminate
SaProt	LLR -9.86	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.42	acceptor gain · deltas
Pangolin	Δ0.24	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4.9	GERP 2.3, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 21 kb · p 0.85 · regional, not allelic
Overall
CADD	26.7	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 0.0165% European (non-Finnish) · 194/1,178,820 alleles

Filtering AF 0.0145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.0124% 200/1,608,946 alleles · ultra-rare exomes 198/1,456,684 · genomes 2/152,262 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0165%	6,076
Remaining individualsnot grpmax-eligible	0.00802%	12,466
African / African-American	0.00133%	74,916

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: CRB2
Protein: p.Leu1237Ile
Coding: c.3709C>A
MANE Select: NM_173689
dbSNP: rs373603388
Type: single nucleotide variant
Location: chr9:123376913 (GRCh38)
Gene constraint: LOEUF 1.202 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.95 · 1 PDB
Residue 1237: a UniProt-annotated variant site (in vmckd; uncertain significance); a UniProt-annotated variant site (in fsgs9; uncertain significance)

Full CRB2 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

CRB2 p.Ala1042Thr Uncertain significance ★★ ⚠ same condition
CRB2 p.Ala1266Pro Uncertain significance ★★ ⚠ same condition
CRB2 p.Ala228Thr Uncertain significance ★★ ⚠ same condition
CRB2 p.Ala26Asp Uncertain significance ★★ ⚠ same condition
CRB2 p.Ala325Val Uncertain significance ★★ ⚠ same condition
CRB2 p.Ala80Thr Uncertain significance ★★ ⚠ same condition
CRB2 p.Ala887Thr Uncertain significance ★★ ⚠ same condition
CRB2 p.Ala914Val 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/crb2-p-leu1237ile (accessed [today's date]).

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