Is VARS2 p.Ala7= (c.21C>T) pathogenic?

VARS2 p.Ala7= (c.21C>T) is classified Benign in VARS2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-02). Common (popmax 35.8%, nfe) — too common for a highly-penetrant pathogenic allele.

VARS2 p.Ala7=

Q: How common is VARS2 p.Ala7= (c.21C>T) in the general population?

VARS2 p.Ala7= (c.21C>T) is common (popmax 35.8%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.21C>T · rs1264302 · VCV380149

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 35.8%, nfe) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.11	GERP -4.1
Overall
CADD	9.314	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 35.8% European (non-Finnish) · 422,549/1,179,924 alleles

Filtering AF 35.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 35.7%

Overall 33.4% 538,211/1,612,758 alleles · common exomes 495,673/1,460,696 · genomes 42,538/152,062 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	38.7%	3
Ashkenazi Jewishnot grpmax-eligible	37.8%	3
European (non-Finnish)grpmax	35.8%	3
Middle Eastern	33.2%	3
Remaining individualsnot grpmax-eligible	31%	3
Amishnot grpmax-eligible	30.8%	3
South Asian	27.5%	4
East Asian	24.2%	4
Admixed American	22.6%	4
African / African-American	12%	8

Finnish 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: VARS2
Protein: p.Ala7=
Coding: c.21C>T
MANE Select: NM_020442
dbSNP: rs1264302
Type: single nucleotide variant
Location: chr6:30914857 (GRCh38)
Structure: AlphaFold pLDDT 88.12

Full VARS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

VARS1 p.Ser7Phe Uncertain significance ★★ ⚠ same residue
VARS1 p.Arg1058Gln Likely pathogenic ★★ ⚠ same type
VARS1 p.Arg1119Cys Pathogenic/Likely pathogenic ★★ same type
VARS1 p.Arg1208Ter Pathogenic/Likely pathogenic ★★ same type
VARS1 p.Gln1039Ter Likely pathogenic ★★ same type
VARS1 p.Trp790Ter Pathogenic/Likely pathogenic ★★ same type
VARS2 c.1480-2A>G Likely pathogenic ★★ same type
VARS2 c.2467-2A>G Pathogenic/Likely pathogenic ★★ 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/vars2-p-ala7 (accessed [today's date]).

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