Is CDS2 p.Ser41Phe (c.122C>T) pathogenic?

CDS2 p.Ser41Phe (c.122C>T) is classified Uncertain significance in CDS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-07). AlphaMissense: likely benign (0.1155); Ultra-rare (popmax 0.0173%, afr).

How common is CDS2 p.Ser41Phe (c.122C>T) in the general population?

CDS2 p.Ser41Phe (c.122C>T) is ultra-rare (popmax 0.0173%, afr) (gnomAD).

What do computational predictors say about CDS2 p.Ser41Phe (c.122C>T)?

AlphaMissense predicts likely benign (score 0.1155) — an in-silico prediction, not a clinical call.

CDS2 p.Ser41Phe

c.122C>T · rs892859277 · VCV2265527

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1155 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0173%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1155	likely benign
REVEL	0.045	moderately benign-leaning
SaProt	LLR -10.13	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP -0.3, phastCons 0.009
Regional constraint	o/e 0.82	unconstrained · MANE · 50 kb · p 0.046 · regional, not allelic
Overall
CADD	17.32	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 0.0173% African / African-American · 13/75,058 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00811%

Overall 0.00124% 20/1,614,206 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0173%	5,774
Admixed American	0.005%	20,011
Remaining individualsnot grpmax-eligible	0.0048%	20,837
European (non-Finnish)	8.47e-05%	1,180,004

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: CDS2
Protein: p.Ser41Phe
Coding: c.122C>T
MANE Select: NM_003818
dbSNP: rs892859277
Type: single nucleotide variant
Location: chr20:5173587 (GRCh38)
Gene constraint: LOEUF 0.944 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.70
Residue 41: the 'disordered' region

Full CDS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDS2 p.Ala346Ser Uncertain significance ★ ⚠ same type
CDS2 p.Ala398Thr Uncertain significance ★ ⚠ same type
CDS2 p.Arg167Trp Uncertain significance ★ ⚠ same type
CDS2 p.Arg311His Uncertain significance ★ ⚠ same type
CDS2 p.Arg429Gln Uncertain significance ★ ⚠ same type
CDS2 p.Asn426Ser Uncertain significance ★ ⚠ same type
CDS2 p.Asp147Gly Uncertain significance ★ ⚠ same type
CDS2 p.Gly378Asp 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/cds2-p-ser41phe (accessed [today's date]).

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