Is CREG2 p.Ala99Pro (c.295G>C) pathogenic?

CREG2 p.Ala99Pro (c.295G>C) is classified Uncertain significance in CREG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-25). AlphaMissense: likely benign (0.0733); Absent from gnomAD v4.1.

How common is CREG2 p.Ala99Pro (c.295G>C) in the general population?

CREG2 p.Ala99Pro (c.295G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CREG2 p.Ala99Pro (c.295G>C)?

AlphaMissense predicts likely benign (score 0.0733) — an in-silico prediction, not a clinical call.

CREG2 p.Ala99Pro

c.295G>C · VCV4656569

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0733 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,273,626)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0733	likely benign
REVEL	0.087	moderately benign-leaning
SaProt	LLR -5.37	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 0.018	GERP 3.1
Regional constraint	o/e 0.97	unconstrained · MANE · 361 bp · p 0.64 · regional, not allelic
Overall
CADD	14.61	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

No allele count reported in gnomAD v4.1 (AN 1,273,626). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CREG2
Protein: p.Ala99Pro
Coding: c.295G>C
MANE Select: NM_153836
Type: single nucleotide variant
Location: chr2:101387163 (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.Ala133Val Uncertain significance ★ ⚠ same type
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.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-ala99pro (accessed [today's date]).

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