Is VCL p.Arg993His (c.2978G>A) pathogenic?

VCL p.Arg993His (c.2978G>A) is classified Uncertain significance in VCL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-24). AlphaMissense: ambiguous (0.3573); Very rare (popmax 0.0011%, sas); Associated with Cardiovascular phenotype.

What condition is associated with VCL p.Arg993His (c.2978G>A)?

VCL p.Arg993His (c.2978G>A) is associated with Cardiovascular phenotype (ClinVar).

How common is VCL p.Arg993His (c.2978G>A) in the general population?

VCL p.Arg993His (c.2978G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about VCL p.Arg993His (c.2978G>A)?

AlphaMissense predicts ambiguous (score 0.3573) — an in-silico prediction, not a clinical call.

VCL p.Arg993His

c.2978G>A · VCV4842809

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3573 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.3573	ambiguous
REVEL	0.398	indeterminate
SaProt	LLR -4.26	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.45	unconstrained · MANE · 6,073 bp · p 2.6e-15 · regional, not allelic
Overall
CADD	33.0	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

Grpmax group 0.0011% South Asian · 1/91,072 alleles

Overall 0.000186% 3/1,613,762 alleles · very rare exomes 2/1,461,636 · genomes 1/152,126 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
South Asiangrpmax	0.0011%	91,072
European (non-Finnish)	8.47e-05%	1,180,022

Ashkenazi Jewish 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.Arg993His
Coding: c.2978G>A
MANE Select: NM_014000
Type: single nucleotide variant
Location: chr10:74114212 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.69 · 37 PDB
Residue 993: the 'c-terminal tail' 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.Arg993Cys Uncertain significance ★★ ⚠ same residue
VCL p.Arg993Leu 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-arg993his (accessed [today's date]).

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