Is VCL p.Phe126Ser (c.377T>C) pathogenic?

VCL p.Phe126Ser (c.377T>C) is classified Uncertain significance in VCL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-19). AlphaMissense: likely pathogenic (0.9973); Very rare (popmax 0.000254%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with VCL p.Phe126Ser (c.377T>C)?

VCL p.Phe126Ser (c.377T>C) is associated with Cardiovascular phenotype (ClinVar).

How common is VCL p.Phe126Ser (c.377T>C) in the general population?

VCL p.Phe126Ser (c.377T>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about VCL p.Phe126Ser (c.377T>C)?

AlphaMissense predicts likely pathogenic (score 0.9973) — an in-silico prediction, not a clinical call.

VCL p.Phe126Ser

c.377T>C · VCV4842806

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9973 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9973	likely pathogenic · top 5% in VCL
REVEL	0.736	pathogenic-leaning
SaProt	LLR -15.45	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.28	constrained · MANE · 73 bp · p 9.4e-05 · regional, not allelic
Overall
CADD	30.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000254% European (non-Finnish) · 3/1,180,014 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,810 alleles · very rare

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: VCL
Protein: p.Phe126Ser
Coding: c.377T>C
MANE Select: NM_014000
Type: single nucleotide variant
Location: chr10:74070807 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.69 · 37 PDB
Residue 126: the 'n-terminal globular head' region; an α-helix

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

VCL p.Phe126= Conflicting classifications of pathogenicity ★ same residue
VCL p.Phe126Leu Uncertain significance ★ ⚠ same residue
VCL c.1352+5G>A Uncertain significance ★★ same condition
VCL c.1543+4A>G Uncertain significance ★★ same condition
VCL c.2132-3C>A Uncertain significance ★★ same condition
VCL c.239+3G>A Uncertain significance ★★ same condition
VCL p.Ala1023Thr Uncertain significance ★★ ⚠ same condition
VCL p.Ala1120Thr Uncertain significance ★★ ⚠ same condition

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-phe126ser (accessed [today's date]).

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