Is CDNF p.Ser121Arg (c.363C>A) pathogenic?

CDNF p.Ser121Arg (c.363C>A) is classified Uncertain significance in CDNF (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-25). AlphaMissense: likely benign (0.272); Ultra-rare (popmax 0.0587%, afr).

How common is CDNF p.Ser121Arg (c.363C>A) in the general population?

CDNF p.Ser121Arg (c.363C>A) is ultra-rare (popmax 0.0587%, afr) (gnomAD).

What do computational predictors say about CDNF p.Ser121Arg (c.363C>A)?

AlphaMissense predicts likely benign (score 0.272) — an in-silico prediction, not a clinical call.

CDNF p.Ser121Arg

c.363C>A · rs139150625 · VCV2393261

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.272 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0587%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.272	likely benign
REVEL	0.339	indeterminate
SaProt	LLR -9.06	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.91	phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 18 kb · p 0.98 · regional, not allelic
Overall
CADD	19.42	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0587% African / African-American · 44/75,016 alleles

Filtering AF 0.0448% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.04%

Overall 0.0031% 50/1,614,024 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0587%	1,705
Admixed American	0.00667%	15,001
Remaining individualsnot grpmax-eligible	0.0032%	31,253

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.Ser121Arg
Coding: c.363C>A
MANE Select: NM_001029954
dbSNP: rs139150625
Type: single nucleotide variant
Location: chr10:14825501 (GRCh38)
Gene constraint: LOEUF 1.332 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.80 · 6 PDB
Residue 121: an α-helix; a disulfide bond

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

Similar variants

CDNF p.Ala135Ser Benign ★★ same type
CDNF p.Tyr167= 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/cdnf-p-ser121arg (accessed [today's date]).

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