Is CERT1 p.Val593Leu (c.1777G>C) pathogenic?

CERT1 p.Val593Leu (c.1777G>C) is classified Uncertain significance in CERT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-25). AlphaMissense: likely pathogenic (0.9611); Absent from gnomAD v4.1.

How common is CERT1 p.Val593Leu (c.1777G>C) in the general population?

CERT1 p.Val593Leu (c.1777G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CERT1 p.Val593Leu (c.1777G>C)?

AlphaMissense predicts likely pathogenic (score 0.9611) — an in-silico prediction, not a clinical call.

CERT1 p.Val593Leu

c.1777G>C · VCV3363419

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9611 · 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	0.9611	likely pathogenic
REVEL	0.62	indeterminate
SaProt	LLR -6.21	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 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 1,760 bp · p 9.1e-05 · regional, not allelic
Overall
CADD	27.9	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: CERT1
Protein: p.Val593Leu
Coding: c.1777G>C
MANE Select: NM_001379029
Type: single nucleotide variant
Location: chr5:75379444 (GRCh38)
Gene constraint: LOEUF 0.656 · pLI 0.10 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 77.75 · 27 PDB
Residue 593: the start domain; an α-helix

Full CERT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CERT1 p.Ser135Phe Likely pathogenic ★★ same type
CERT1 p.Thr166Ala Pathogenic/Likely pathogenic ★★ ⚠ same type
CERT1 c.-195C>T Uncertain significance ★★ same type
CERT1 p.Ala538Val Uncertain significance ★★ ⚠ same type
CERT1 p.Asp80Asn Uncertain significance ★★ ⚠ same type
CERT1 p.Cys185Phe Uncertain significance ★★ ⚠ same type
CERT1 p.Gly452Asp Uncertain significance ★★ ⚠ same type
CERT1 p.Lys48Asn 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/cert1-p-val593leu (accessed [today's date]).

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