Is CREG2 p.Ala133Val (c.398C>T) pathogenic?

CREG2 p.Ala133Val (c.398C>T) is classified Uncertain significance in CREG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-16). AlphaMissense: likely benign (0.1067); Ultra-rare (popmax 0.0367%, sas).

How common is CREG2 p.Ala133Val (c.398C>T) in the general population?

CREG2 p.Ala133Val (c.398C>T) is ultra-rare (popmax 0.0367%, sas) (gnomAD).

What do computational predictors say about CREG2 p.Ala133Val (c.398C>T)?

AlphaMissense predicts likely benign (score 0.1067) — an in-silico prediction, not a clinical call.

CREG2 p.Ala133Val

c.398C>T · rs1051625142 · VCV3077381

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1067 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0367%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1067	likely benign
REVEL	0.045	moderately benign-leaning
SaProt	LLR -6.68	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 4.1	GERP 4.4, phastCons 1
Regional constraint	o/e 0.40	unconstrained · MANE · 3,399 bp · p 0.00028 · regional, not allelic
Overall
CADD	21.6	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 0.0367% South Asian · 9/24,528 alleles

Filtering AF 0.0191% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0143%

Overall 0.00102% 11/1,080,906 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0367%	2,725
Remaining individualsnot grpmax-eligible	0.00218%	45,820
European (non-Finnish)	0.000101%	989,188

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: CREG2
Protein: p.Ala133Val
Coding: c.398C>T
MANE Select: NM_153836
dbSNP: rs1051625142
Type: single nucleotide variant
Location: chr2:101387060 (GRCh38)
Gene constraint: LOEUF 1.508 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.48

Full CREG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CREG2 p.Ala290Ser Uncertain significance ★ ⚠ same type
CREG2 p.Ala290Val Uncertain significance ★ ⚠ same type
CREG2 p.Ala29Ser Uncertain significance ★ ⚠ same type
CREG2 p.Ala29Thr Uncertain significance ★ ⚠ same type
CREG2 p.Ala30Glu Uncertain significance ★ ⚠ same type
CREG2 p.Ala92Val Uncertain significance ★ ⚠ same type
CREG2 p.Ala99Pro Uncertain significance ★ ⚠ same type
CREG2 p.Arg107Leu 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/creg2-p-ala133val (accessed [today's date]).

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