Is RBPJ p.Pro337Ser (c.1009C>T) pathogenic?

RBPJ p.Pro337Ser (c.1009C>T) is classified Uncertain significance in RBPJ (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-25). AlphaMissense: ambiguous (0.367); Very rare (popmax 0.000424%, nfe).

How common is RBPJ p.Pro337Ser (c.1009C>T) in the general population?

RBPJ p.Pro337Ser (c.1009C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about RBPJ p.Pro337Ser (c.1009C>T)?

AlphaMissense predicts ambiguous (score 0.367) — an in-silico prediction, not a clinical call.

RBPJ p.Pro337Ser

c.1009C>T · VCV3696402

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.367 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.367	ambiguous
REVEL	0.26	benign-leaning
SaProt	LLR -11.06	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense 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 2.1, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 40 bp · p 0.8 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P350S vs ClinVar P337S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,982 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,613,942 alleles · very rare exomes 3/1,461,804 · genomes 2/152,138 · 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: RBPJ
Protein: p.Pro337Ser
Coding: c.1009C>T
MANE Select: NM_015874
Type: single nucleotide variant
Location: chr4:26430018 (GRCh38)
Gene constraint: LOEUF 0.267 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.76 · 4 PDB

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

Similar variants

RBPJ p.Arg17Gln Uncertain significance ★★ ⚠ same type
RBPJ p.Arg181Ter Uncertain significance ★★ same type
RBPJ p.Asp77Asn Uncertain significance ★★ ⚠ same type
RBPJ p.Glu459Lys Uncertain significance ★★ ⚠ same type
RBPJ p.Gly10Val Uncertain significance ★★ ⚠ same type
RBPJ p.Pro86Leu Uncertain significance ★★ same type
RBPJ p.Thr482Ile Uncertain significance ★★ ⚠ same type
RBPJ c.1045-97T>A Likely benign ★★ 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/rbpj-p-pro337ser (accessed [today's date]).

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