Is CGREF1 p.Phe142Leu (c.424T>C) pathogenic?

CGREF1 p.Phe142Leu (c.424T>C) is classified Uncertain significance in CGREF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-11). AlphaMissense: likely pathogenic (0.7805); Absent from gnomAD v4.1.

How common is CGREF1 p.Phe142Leu (c.424T>C) in the general population?

CGREF1 p.Phe142Leu (c.424T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CGREF1 p.Phe142Leu (c.424T>C)?

AlphaMissense predicts likely pathogenic (score 0.7805) — an in-silico prediction, not a clinical call.

CGREF1 p.Phe142Leu

c.424T>C · VCV4001978

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7805 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7805	likely pathogenic · top 9% in CGREF1
REVEL	0.307	indeterminate
SaProt	LLR -5.30	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP -0.95, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 2,817 bp · p 0.22 · regional, not allelic
Overall
CADD	17.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CGREF1
Protein: p.Phe142Leu
Coding: c.424T>C
MANE Select: NM_006569
Type: single nucleotide variant
Location: chr2:27101807 (GRCh38)
Gene constraint: LOEUF 1.364 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.75
Residue 142: the ef-hand 2 domain

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-phe142leu (accessed [today's date]).

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