Is CDSN p.Ser408Ala (c.1222T>G) pathogenic?

CDSN p.Ser408Ala (c.1222T>G) is classified Benign in CDSN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-04). Common (popmax 32.7%, sas) — too common for a highly-penetrant pathogenic allele.

CDSN p.Ser408Ala

Q: How common is CDSN p.Ser408Ala (c.1222T>G) in the general population?

CDSN p.Ser408Ala (c.1222T>G) is common (popmax 32.7%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1222T>G · rs1042127 · VCV1236988

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 32.7%, sas) — 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.
REVEL	0.032	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	phastCons 0.78
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 32.7% South Asian · 29,322/89,730 alleles

Filtering AF 32.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 32.2%

Overall 17.7% 284,011/1,600,850 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	32.7%	3
Ashkenazi Jewishnot grpmax-eligible	27%	4
Middle Eastern	24.9%	4
East Asian	19.9%	5
Admixed American	19.7%	5
Finnishnot grpmax-eligible	19.5%	5
Remaining individualsnot grpmax-eligible	18.2%	6
European (non-Finnish)	16.5%	6
African / African-American	10.9%	9
Amishnot grpmax-eligible	8%	12

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: CDSN
Protein: p.Ser408Ala
Coding: c.1222T>G
MANE Select: NM_001264
dbSNP: rs1042127
Type: single nucleotide variant
Location: chr6:31116393 (GRCh38)
Gene constraint: LOEUF 0.77 · pLI 0.08 (gnomAD)
Structure: AlphaFold pLDDT 38.13
Residue 408: a UniProt-annotated variant site (in allele 1.51); the 'disordered' region

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

Similar variants

CDSN p.Ser408= Likely benign ★ same residue
CDSN p.Lys59Ter Pathogenic ★★ same type
CDSN p.Cys423Ser Uncertain significance ★★ same type
CDSN p.Gly335Ala Uncertain significance ★★ same type
CDSN p.Pro226Ser Uncertain significance ★★ same type
CDSN p.Pro282Thr Uncertain significance ★★ same type
CDSN p.Pro447Leu Uncertain significance ★★ same type
CDSN p.Pro471Leu 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/cdsn-p-ser408ala (accessed [today's date]).

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