Is CRB2 p.Ser394Phe (c.1181C>T) pathogenic?

CRB2 p.Ser394Phe (c.1181C>T) is classified Uncertain significance in CRB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-04). AlphaMissense: likely benign (0.3308); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CRB2 p.Ser394Phe (c.1181C>T)?

CRB2 p.Ser394Phe (c.1181C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CRB2 p.Ser394Phe (c.1181C>T) in the general population?

CRB2 p.Ser394Phe (c.1181C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CRB2 p.Ser394Phe (c.1181C>T)?

AlphaMissense predicts likely benign (score 0.3308) — an in-silico prediction, not a clinical call.

CRB2 p.Ser394Phe

c.1181C>T · VCV4616550

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3308 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3308	likely benign
REVEL	0.623	indeterminate
SaProt	LLR -12.87	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 21 kb · p 0.85 · regional, not allelic
Overall
CADD	27.2	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 8.47e-05% European (non-Finnish) · 1/1,180,008 alleles

Overall 6.2e-05% 1/1,613,320 alleles · very rare exomes 1/1,460,976 · genomes 0/152,344 · 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: CRB2
Protein: p.Ser394Phe
Coding: c.1181C>T
MANE Select: NM_173689
Type: single nucleotide variant
Location: chr9:123370234 (GRCh38)
Gene constraint: LOEUF 1.202 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.95 · 1 PDB
Residue 394: the egf-like 8; calcium-binding domain; 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
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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-ser394phe (accessed [today's date]).

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