Is CREG2 p.Met239Thr (c.716T>C) pathogenic?

CREG2 p.Met239Thr (c.716T>C) is classified Uncertain significance in CREG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-15). AlphaMissense: ambiguous (0.4471); Ultra-rare (popmax 0.0156%, eas).

How common is CREG2 p.Met239Thr (c.716T>C) in the general population?

CREG2 p.Met239Thr (c.716T>C) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about CREG2 p.Met239Thr (c.716T>C)?

AlphaMissense predicts ambiguous (score 0.4471) — an in-silico prediction, not a clinical call.

CREG2 p.Met239Thr

c.716T>C · VCV4829394

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4471 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4471	ambiguous
REVEL	0.227	benign-leaning
SaProt	LLR -6.79	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 33 kb · p 0.76 · regional, not allelic
Overall
CADD	24.1	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 0.0156% East Asian · 7/44,846 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.000687% 10/1,456,146 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,407
Remaining individualsnot grpmax-eligible	0.00482%	20,766

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.Met239Thr
Coding: c.716T>C
MANE Select: NM_153836
Type: single nucleotide variant
Location: chr2:101355262 (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.Ala99Pro 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-met239thr (accessed [today's date]).

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