Is CGREF1 p.Pro21Leu (c.62C>T) pathogenic?

CGREF1 p.Pro21Leu (c.62C>T) is classified Uncertain significance in CGREF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-07). AlphaMissense: ambiguous (0.5187); Very rare (popmax 0.00224%, eas).

How common is CGREF1 p.Pro21Leu (c.62C>T) in the general population?

CGREF1 p.Pro21Leu (c.62C>T) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about CGREF1 p.Pro21Leu (c.62C>T)?

AlphaMissense predicts ambiguous (score 0.5187) — an in-silico prediction, not a clinical call.

CGREF1 p.Pro21Leu

c.62C>T · VCV4001974

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5187 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5187	ambiguous
REVEL	0.132	moderately benign-leaning
SaProt	LLR -9.39	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 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 2,817 bp · p 0.22 · regional, not allelic
Overall
CADD	26.7	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 0.00224% East Asian · 1/44,580 alleles

Overall 0.000141% 2/1,415,990 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,580
Remaining individualsnot grpmax-eligible	0.00165%	60,470

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.Pro21Leu
Coding: c.62C>T
MANE Select: NM_006569
Type: single nucleotide variant
Location: chr2:27104305 (GRCh38)
Gene constraint: LOEUF 1.364 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.75

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

Similar variants

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
KHK c.*79G>A 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-pro21leu (accessed [today's date]).

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