Is CREB5 p.Val398Phe (c.1192G>T) pathogenic?

CREB5 p.Val398Phe (c.1192G>T) is classified Uncertain significance in CREB5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-23). AlphaMissense: likely pathogenic (0.7186); Very rare (popmax 0.00271%, nfe).

How common is CREB5 p.Val398Phe (c.1192G>T) in the general population?

CREB5 p.Val398Phe (c.1192G>T) is very rare (popmax 0.00271%, nfe) (gnomAD).

What do computational predictors say about CREB5 p.Val398Phe (c.1192G>T)?

AlphaMissense predicts likely pathogenic (score 0.7186) — an in-silico prediction, not a clinical call.

CREB5 p.Val398Phe

c.1192G>T · rs781328727 · VCV3077329

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7186 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00271%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7186	likely pathogenic
REVEL	0.242	benign-leaning
SaProt	LLR -11.83	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.2, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 9,924 bp · p 0.14 · regional, not allelic
Overall
CADD	32.0	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 0.00271% European (non-Finnish) · 32/1,180,044 alleles

Filtering AF 0.00196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00168%

Overall 0.00211% 34/1,614,052 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,242
European (non-Finnish)grpmax	0.00271%	36,876

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val398Phe
Coding: c.1192G>T
MANE Select: NM_182898
dbSNP: rs781328727
Type: single nucleotide variant
Location: chr7:28809352 (GRCh38)
Gene constraint: LOEUF 0.421 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 57.95
Residue 398: the bzip domain

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-val398phe (accessed [today's date]).

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