Is CREB3L2 p.Pro207Leu (c.620C>T) pathogenic?

CREB3L2 p.Pro207Leu (c.620C>T) is classified Uncertain significance in CREB3L2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-12). AlphaMissense: likely pathogenic (0.9292); Very rare (popmax 0.00155%, afr).

How common is CREB3L2 p.Pro207Leu (c.620C>T) in the general population?

CREB3L2 p.Pro207Leu (c.620C>T) is very rare (popmax 0.00155%, afr) (gnomAD).

What do computational predictors say about CREB3L2 p.Pro207Leu (c.620C>T)?

AlphaMissense predicts likely pathogenic (score 0.9292) — an in-silico prediction, not a clinical call.

CREB3L2 p.Pro207Leu

c.620C>T · rs1585613637 · VCV2229772

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9292 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00155%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9292	likely pathogenic
REVEL	0.642	indeterminate
SaProt	LLR -10.16	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 96 kb · p 0.38 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00155% African / African-American · 1/64,580 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000188%

Overall 0.000632% 8/1,266,240 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00155%	64,580
European (non-Finnish)	0.000702%	142,545

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: CREB3L2
Protein: p.Pro207Leu
Coding: c.620C>T
MANE Select: NM_194071
dbSNP: rs1585613637
Type: single nucleotide variant
Location: chr7:137908400 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 55.95
Residue 207: the 'disordered' region

Full CREB3L2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CREB3L2 p.Ala294Ser Uncertain significance ★ ⚠ same type
CREB3L2 p.Arg223Cys Uncertain significance ★ ⚠ same type
CREB3L2 p.Arg241Gln Uncertain significance ★ ⚠ same type
CREB3L2 p.Arg299Gln Uncertain significance ★ ⚠ same type
CREB3L2 p.Arg348Ser Uncertain significance ★ ⚠ same type
CREB3L2 p.Arg90Gln Uncertain significance ★ ⚠ same type
CREB3L2 p.Arg90Trp Uncertain significance ★ ⚠ same type
CREB3L2 p.Asn304Ser 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/creb3l2-p-pro207leu (accessed [today's date]).

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