Is CREB3L4 p.Pro320Leu (c.959C>T) pathogenic?

CREB3L4 p.Pro320Leu (c.959C>T) is classified Uncertain significance in CREB3L4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-04). AlphaMissense: likely benign (0.0838); Ultra-rare (popmax 0.0533%, sas).

How common is CREB3L4 p.Pro320Leu (c.959C>T) in the general population?

CREB3L4 p.Pro320Leu (c.959C>T) is ultra-rare (popmax 0.0533%, sas) (gnomAD).

What do computational predictors say about CREB3L4 p.Pro320Leu (c.959C>T)?

AlphaMissense predicts likely benign (score 0.0838) — an in-silico prediction, not a clinical call.

CREB3L4 p.Pro320Leu

c.959C>T · rs763007313 · VCV2517545

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0838 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0533%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0838	likely benign
REVEL	0.087	moderately benign-leaning
SaProt	LLR -6.97	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	phastCons 0.041
Regional constraint	o/e 0.95	unconstrained · MANE · 5,536 bp · p 0.28 · regional, not allelic
Overall
CADD	20.4	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 0.0533% South Asian · 48/90,098 alleles

Filtering AF 0.0412% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.037%

Overall 0.00405% 59/1,455,872 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0533%	1,877
East Asian	0.00223%	44,816
Remaining individualsnot grpmax-eligible	0.00161%	62,288
European (non-Finnish)	0.000765%	130,768

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: CREB3L4
Protein: p.Pro320Leu
Coding: c.959C>T
MANE Select: NM_001255978
dbSNP: rs763007313
Type: single nucleotide variant
Location: chr1:153973681 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.56

Full CREB3L4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CREB3 c.697-5T>C Benign ★★ same type
CREB3 p.Asn222= Benign ★★ same type
CREB3 p.Ala113Val Uncertain significance ★ ⚠ same type
CREB3 p.Arg153Cys Uncertain significance ★ ⚠ same type
CREB3 p.Arg155Pro Uncertain significance ★ ⚠ same type
CREB3 p.Arg155Trp Uncertain significance ★ ⚠ same type
CREB3 p.Arg168Cys Uncertain significance ★ ⚠ same type
CREB3 p.Arg264Cys Uncertain significance ★ ⚠ 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/creb3l4-p-pro320leu (accessed [today's date]).

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