Is CITED2 p.Ala7= (c.21C>A) pathogenic?

CITED2 p.Ala7= (c.21C>A) is classified Benign in CITED2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-04-26). Common (popmax 19.5%, nfe) — too common for a highly-penetrant pathogenic allele.

CITED2 p.Ala7=

Q: How common is CITED2 p.Ala7= (c.21C>A) in the general population?

CITED2 p.Ala7= (c.21C>A) is common (popmax 19.5%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.21C>A · rs1131400 · VCV1231089

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 19.5%, 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 8.5	GERP 1.5, phastCons 1
Overall
CADD	12.51	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 19.5% European (non-Finnish) · 229,919/1,179,666 alleles

Filtering AF 19.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 19.4%

Overall 18.5% 295,963/1,598,790 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	21.2%	5
Ashkenazi Jewishnot grpmax-eligible	20.5%	5
European (non-Finnish)grpmax	19.5%	5
Amishnot grpmax-eligible	19.2%	5
Middle Eastern	17.7%	6
Remaining individualsnot grpmax-eligible	17.5%	6
Admixed American	17.5%	6
South Asian	15.9%	6
African / African-American	14.2%	7
East Asian	3.68%	27

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: CITED2
Protein: p.Ala7=
Coding: c.21C>A
MANE Select: NM_006079
dbSNP: rs1131400
Type: single nucleotide variant
Location: chr6:139373924 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI 0.90 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 52.07 · 4 PDB

Full CITED2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CITED2 p.Ala7Pro Uncertain significance ★ ⚠ same residue
CITED2 p.Ala7Val Uncertain significance ★ ⚠ same residue
CITED2 p.Ala25Pro Uncertain significance ★★ ⚠ same type
CITED2 p.Ala25Val Uncertain significance ★★ ⚠ same type
CITED2 p.Pro128Ser Uncertain significance ★★ ⚠ same type
CITED2 p.Gly194= Benign/Likely benign ★★ same type
CITED2 p.His160Leu Benign/Likely benign ★★ same type
CITED2 p.His46= Likely benign ★★ 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/cited2-p-ala7 (accessed [today's date]).

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