Is CGN p.Ala61Ser (c.181G>T) pathogenic?

CGN p.Ala61Ser (c.181G>T) is classified Uncertain significance in CGN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-07). Ultra-rare (popmax 0.0164%, mid).

How common is CGN p.Ala61Ser (c.181G>T) in the general population?

CGN p.Ala61Ser (c.181G>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

CGN p.Ala61Ser

c.181G>T · rs751915500 · VCV2212612

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.115	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 16 kb · p 0.38 · regional, not allelic
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00297% 48/1,614,026 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0777%	1,287
Middle Easterngrpmax	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.008%	12,498
South Asian	0.00329%	30,363
Admixed American	0.00167%	60,004
African / African-American	0.00134%	74,894
European (non-Finnish)	0.00119%	84,288

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: CGN
Protein: p.Ala61Ser
Coding: c.181G>T
MANE Select: NM_020770
dbSNP: rs751915500
Type: single nucleotide variant
Location: chr1:151518700 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.44
Residue 61: the 'head' region; the 'interaction with tjp1/zo1' region

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

Similar variants

CGN p.Ala357= Benign/Likely benign ★★ same type
CGN p.Arg11Trp Likely benign ★★ same type
CGN p.Arg227Trp Likely benign ★★ same type
CGN p.Arg547Lys Benign ★★ same type
CGN p.Arg973Gln Benign ★★ same type
CGN p.Glu771Lys Benign/Likely benign ★★ same type
CGN p.Ile60= Benign ★★ same type
CGN p.Ala1035Thr Uncertain significance ★ 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/cgn-p-ala61ser (accessed [today's date]).

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