Is CDNF p.Ala135Ser (c.403G>T) pathogenic?

CDNF p.Ala135Ser (c.403G>T) is classified Benign in CDNF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0788); Common (popmax 5.12%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CDNF p.Ala135Ser (c.403G>T)?

AlphaMissense predicts likely benign (score 0.0788) — an in-silico prediction, not a clinical call.

CDNF p.Ala135Ser

Q: How common is CDNF p.Ala135Ser (c.403G>T) in the general population?

CDNF p.Ala135Ser (c.403G>T) is common (popmax 5.12%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.403G>T · rs61740068 · VCV786149

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0788 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.12%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0788	likely benign
REVEL	0.1	moderately benign-leaning
SaProt	LLR -5.15	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 18 kb · p 0.98 · regional, not allelic
Overall
CADD	17.08	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 5.12% African / African-American · 3,829/74,770 alleles

Filtering AF 4.99% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.93%

Overall 0.272% 4,383/1,608,798 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.12%	20
Admixed American	0.38%	263
Remaining individualsnot grpmax-eligible	0.372%	269
Middle Eastern	0.132%	756
South Asian	0.0535%	1,868
European (non-Finnish)	0.00382%	26,193

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: CDNF
Protein: p.Ala135Ser
Coding: c.403G>T
MANE Select: NM_001029954
dbSNP: rs61740068
Type: single nucleotide variant
Location: chr10:14820141 (GRCh38)
Gene constraint: LOEUF 1.332 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.80 · 6 PDB
Residue 135: an α-helix

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

Similar variants

CDNF p.Tyr167= Benign ★★ same type
CDNF p.Ser121Arg 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/cdnf-p-ala135ser (accessed [today's date]).

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