Is CREG1 p.Pro47Leu (c.140C>T) pathogenic?

CREG1 p.Pro47Leu (c.140C>T) is classified Uncertain significance in CREG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-21). AlphaMissense: likely benign (0.1006); Ultra-rare (popmax 0.0739%, mid).

How common is CREG1 p.Pro47Leu (c.140C>T) in the general population?

CREG1 p.Pro47Leu (c.140C>T) is ultra-rare (popmax 0.0739%, mid) (gnomAD).

What do computational predictors say about CREG1 p.Pro47Leu (c.140C>T)?

AlphaMissense predicts likely benign (score 0.1006) — an in-silico prediction, not a clinical call.

CREG1 p.Pro47Leu

c.140C>T · rs944002481 · VCV2225923

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1006 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0739%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1006	likely benign
REVEL	0.045	moderately benign-leaning
SaProt	LLR -9.10	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 5.8	GERP -0.47, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 11 kb · p 0.16 · regional, not allelic
Overall
CADD	24.4	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 0.0739% Middle Eastern · 3/4,060 alleles

Filtering AF 0.0201% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0107%

Overall 0.00163% 23/1,414,394 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0739%	1,353
Remaining individualsnot grpmax-eligible	0.00553%	18,082
Finnishnot grpmax-eligible	0.0048%	20,850
African / African-American	0.0015%	66,882
South Asian	0.00147%	68,054
European (non-Finnish)	0.00119%	83,774

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: CREG1
Protein: p.Pro47Leu
Coding: c.140C>T
MANE Select: NM_003851
dbSNP: rs944002481
Type: single nucleotide variant
Location: chr1:167553602 (GRCh38)
Gene constraint: LOEUF 1.795 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.08 · 1 PDB

Full CREG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CREG1 p.Ala11Val Uncertain significance ★ ⚠ same type
CREG1 p.Ala130Ser Uncertain significance ★ ⚠ same type
CREG1 p.Ala15Thr Uncertain significance ★ ⚠ same type
CREG1 p.Ala18Ser Uncertain significance ★ ⚠ same type
CREG1 p.Ala23Val Uncertain significance ★ ⚠ same type
CREG1 p.Ala29Ser Uncertain significance ★ ⚠ same type
CREG1 p.Ala56Glu Uncertain significance ★ ⚠ same type
CREG1 p.Ala70Ser 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/creg1-p-pro47leu (accessed [today's date]).

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