Is CREB5 p.Val488Met (c.1462G>A) pathogenic?

CREB5 p.Val488Met (c.1462G>A) is classified Uncertain significance in CREB5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-05). AlphaMissense: likely benign (0.0937); Very rare (popmax 0.00891%, eas).

How common is CREB5 p.Val488Met (c.1462G>A) in the general population?

CREB5 p.Val488Met (c.1462G>A) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about CREB5 p.Val488Met (c.1462G>A)?

AlphaMissense predicts likely benign (score 0.0937) — an in-silico prediction, not a clinical call.

CREB5 p.Val488Met

c.1462G>A · rs759707007 · VCV3077331

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0937 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0937	likely benign
REVEL	0.192	benign-leaning
SaProt	LLR -7.02	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.26	donor gain · deltas
Pangolin	Δ0.51	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 9,924 bp · p 0.14 · regional, not allelic
Overall
CADD	26.4	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 0.00891% East Asian · 4/44,872 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00031% 5/1,613,748 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,218
European (non-Finnish)	8.48e-05%	1,179,908

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: CREB5
Protein: p.Val488Met
Coding: c.1462G>A
MANE Select: NM_182898
dbSNP: rs759707007
Type: single nucleotide variant
Location: chr7:28819214 (GRCh38)
Gene constraint: LOEUF 0.421 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 57.95

Full CREB5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CREB5 p.Ala193Thr Uncertain significance ★ ⚠ same type
CREB5 p.Ala221Asp Uncertain significance ★ ⚠ same type
CREB5 p.Arg152Cys Uncertain significance ★ ⚠ same type
CREB5 p.Arg200Gln Uncertain significance ★ ⚠ same type
CREB5 p.Arg265Gln Uncertain significance ★ ⚠ same type
CREB5 p.Arg26Cys Uncertain significance ★ ⚠ same type
CREB5 p.Arg26His Uncertain significance ★ ⚠ same type
CREB5 p.Arg365Cys 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/creb5-p-val488met (accessed [today's date]).

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