Is VCL p.Ala585Pro (c.1753G>C) pathogenic?

VCL p.Ala585Pro (c.1753G>C) is classified Uncertain significance in VCL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-27). AlphaMissense: likely pathogenic (0.6675); Absent from gnomAD v4.1.

How common is VCL p.Ala585Pro (c.1753G>C) in the general population?

VCL p.Ala585Pro (c.1753G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about VCL p.Ala585Pro (c.1753G>C)?

AlphaMissense predicts likely pathogenic (score 0.6675) — an in-silico prediction, not a clinical call.

VCL p.Ala585Pro

c.1753G>C · VCV3337737

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6675 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6675	likely pathogenic
REVEL	0.368	indeterminate
SaProt	LLR -8.53	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.8	GERP -0.32, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 38 kb · p 3e-08 · regional, not allelic
Overall
CADD	21.3	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: VCL
Protein: p.Ala585Pro
Coding: c.1753G>C
MANE Select: NM_014000
Type: single nucleotide variant
Location: chr10:74097213 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.69 · 37 PDB
Residue 585: the 'n-terminal globular head' region; the '3 x 112 aa tandem repeats' region; an α-helix

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

Similar variants

VCL c.1176+4G>C Uncertain significance ★★ same type
VCL c.1352+5G>A Uncertain significance ★★ same type
VCL c.1543+1G>T Uncertain significance ★★ same type
VCL c.1543+4A>G Uncertain significance ★★ same type
VCL c.1743+6A>G Uncertain significance ★★ same type
VCL c.1744-1G>T Uncertain significance ★★ same type
VCL c.2022+5G>T Uncertain significance ★★ same type
VCL c.2023-1G>C 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/vcl-p-ala585pro (accessed [today's date]).

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