Is VCL p.Phe626Ser (c.1877T>C) pathogenic?

VCL p.Phe626Ser (c.1877T>C) is classified Uncertain significance in VCL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-04-07). AlphaMissense: likely pathogenic (0.9887); Very rare (popmax 0.000339%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with VCL p.Phe626Ser (c.1877T>C)?

VCL p.Phe626Ser (c.1877T>C) is associated with Cardiovascular phenotype, dilated cardiomyopathy 1W (ClinVar).

How common is VCL p.Phe626Ser (c.1877T>C) in the general population?

VCL p.Phe626Ser (c.1877T>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about VCL p.Phe626Ser (c.1877T>C)?

AlphaMissense predicts likely pathogenic (score 0.9887) — an in-silico prediction, not a clinical call.

VCL p.Phe626Ser

c.1877T>C · rs2549229657 · VCV1964973

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9887 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9887	likely pathogenic
REVEL	0.694	pathogenic-leaning
SaProt	LLR -13.16	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 38 kb · p 3e-08 · regional, not allelic
Overall
CADD	28.2	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 0.000339% European (non-Finnish) · 4/1,179,982 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,614,028 alleles · very rare exomes 5/1,461,788 · genomes 0/152,240 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,504
European (non-Finnish)grpmax	0.000339%	294,996

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe626Ser
Coding: c.1877T>C
MANE Select: NM_014000
dbSNP: rs2549229657
Type: single nucleotide variant
Location: chr10:74100952 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.69 · 37 PDB
Residue 626: 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

Also linked: dilated cardiomyopathy 1W

Similar variants

VCL p.Phe626_Asp627insGlu Uncertain significance ★★ same residue
VCL c.1176+4G>C Uncertain significance ★★ same condition
VCL c.1352+5G>A Uncertain significance ★★ same condition
VCL c.1543+1G>T Uncertain significance ★★ same condition
VCL c.1543+4A>G Uncertain significance ★★ same condition
VCL c.1743+6A>G Uncertain significance ★★ same condition
VCL c.1744-1G>T Uncertain significance ★★ same condition
VCL c.2022+5G>T 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-phe626ser (accessed [today's date]).

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