Is CREB5 p.Glu77Lys (c.229G>A) pathogenic?

CREB5 p.Glu77Lys (c.229G>A) is classified Uncertain significance in CREB5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-02). AlphaMissense: likely pathogenic (0.857); Very rare (popmax 0.00267%, afr).

How common is CREB5 p.Glu77Lys (c.229G>A) in the general population?

CREB5 p.Glu77Lys (c.229G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CREB5 p.Glu77Lys (c.229G>A)?

AlphaMissense predicts likely pathogenic (score 0.857) — an in-silico prediction, not a clinical call.

CREB5 p.Glu77Lys

c.229G>A · VCV3496970

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.857 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.857	likely pathogenic
REVEL	0.171	moderately benign-leaning
SaProt	LLR -13.04	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 2.5, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 396 kb · p 0.013 · regional, not allelic
Overall
CADD	29.2	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 0.00267% African / African-American · 2/74,904 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000806% 13/1,612,702 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,452
Remaining individualsnot grpmax-eligible	0.0016%	62,420
European (non-Finnish)	0.000848%	117,903

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.Glu77Lys
Coding: c.229G>A
MANE Select: NM_182898
Type: single nucleotide variant
Location: chr7:28507675 (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-glu77lys (accessed [today's date]).

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