Is CGREF1 p.Pro293Thr (c.877C>A) pathogenic?

CGREF1 p.Pro293Thr (c.877C>A) is classified Uncertain significance in CGREF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-22). AlphaMissense: likely benign (0.0882); Rare (popmax 0.106%, afr).

How common is CGREF1 p.Pro293Thr (c.877C>A) in the general population?

CGREF1 p.Pro293Thr (c.877C>A) is rare (popmax 0.106%, afr) (gnomAD).

What do computational predictors say about CGREF1 p.Pro293Thr (c.877C>A)?

AlphaMissense predicts likely benign (score 0.0882) — an in-silico prediction, not a clinical call.

CGREF1 p.Pro293Thr

c.877C>A · VCV4001972

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0882 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.106%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0882	likely benign
REVEL	0.254	benign-leaning
SaProt	LLR -7.06	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 5.5	GERP 0.95, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 106 bp · p 0.9 · regional, not allelic
Overall
CADD	18.89	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 0.106% African / African-American · 79/74,856 alleles

Filtering AF 0.0868% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0798%

Overall 0.00633% 102/1,612,010 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.106%	948
Middle Eastern	0.0659%	1,517
Admixed American	0.0167%	5,973
Remaining individualsnot grpmax-eligible	0.0128%	7,799
South Asian	0.0011%	90,828

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: CGREF1
Protein: p.Pro293Thr
Coding: c.877C>A
MANE Select: NM_006569
Type: single nucleotide variant
Location: chr2:27101354 (GRCh38)
Gene constraint: LOEUF 1.364 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.75
Residue 293: the 'disordered' region

Full CGREF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KHK p.Gly293= Benign/Likely benign ★★ same residue
KHK c.*469G>A Uncertain significance ★★ same type
KHK p.Ala230Thr Uncertain significance ★★ ⚠ same type
KHK p.Glu276Lys Uncertain significance ★★ ⚠ same type
KHK c.*540G>C Benign ★★ same type
KHK c.*580T>C Benign ★★ same type
KHK c.*754T>C Benign ★★ same type
KHK c.*767C>T Benign ★★ 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/cgref1-p-pro293thr (accessed [today's date]).

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