Is CREBL2 p.Val7Ala (c.20T>C) pathogenic?

CREBL2 p.Val7Ala (c.20T>C) is classified Uncertain significance in CREBL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-09). AlphaMissense: likely benign (0.0781); Ultra-rare (popmax 0.0654%, afr).

How common is CREBL2 p.Val7Ala (c.20T>C) in the general population?

CREBL2 p.Val7Ala (c.20T>C) is ultra-rare (popmax 0.0654%, afr) (gnomAD).

What do computational predictors say about CREBL2 p.Val7Ala (c.20T>C)?

AlphaMissense predicts likely benign (score 0.0781) — an in-silico prediction, not a clinical call.

CREBL2 p.Val7Ala

c.20T>C · VCV4656549

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0781 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0654%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0781	likely benign
REVEL	0.096	moderately benign-leaning
SaProt	LLR -6.01	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 4.4	phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 24 kb · p 0.81 · regional, not allelic
Overall
CADD	19.44	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 0.0654% African / African-American · 49/74,962 alleles

Filtering AF 0.0507% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0456%

Overall 0.00354% 57/1,609,520 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0654%	1,530
Admixed American	0.00677%	14,774
Remaining individualsnot grpmax-eligible	0.00321%	31,181
European (non-Finnish)	0.00017%	588,821

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: CREBL2
Protein: p.Val7Ala
Coding: c.20T>C
MANE Select: NM_001310
Type: single nucleotide variant
Location: chr12:12635781 (GRCh38)
Gene constraint: LOEUF 0.427 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 76.59
Residue 7: the 'disordered' region

Full CREBL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CREBL2 p.Arg58Ter Likely pathogenic ★ same type
CREBL2 p.Ala64Ser Uncertain significance ★ ⚠ same type
CREBL2 p.Asp114His Uncertain significance ★ ⚠ same type
CREBL2 p.Gln81Lys Uncertain significance ★ ⚠ same type
CREBL2 p.Glu87Asp Uncertain significance ★ ⚠ same type
CREBL2 p.Gly15Ser Uncertain significance ★ ⚠ same type
CREBL2 p.Met79Val Uncertain significance ★ ⚠ same type
CREBL2 p.Ser100Cys 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/crebl2-p-val7ala (accessed [today's date]).

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