Is CDS2 p.Met99Thr (c.296T>C) pathogenic?

CDS2 p.Met99Thr (c.296T>C) is classified Uncertain significance in CDS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-04). AlphaMissense: likely benign (0.2231); Absent from gnomAD v4.1.

How common is CDS2 p.Met99Thr (c.296T>C) in the general population?

CDS2 p.Met99Thr (c.296T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDS2 p.Met99Thr (c.296T>C)?

AlphaMissense predicts likely benign (score 0.2231) — an in-silico prediction, not a clinical call.

CDS2 p.Met99Thr

c.296T>C · VCV4651686

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2231 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2231	likely benign
REVEL	0.199	benign-leaning
SaProt	LLR -9.17	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 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 50 kb · p 0.046 · regional, not allelic
Overall
CADD	23.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CDS2
Protein: p.Met99Thr
Coding: c.296T>C
MANE Select: NM_003818
Type: single nucleotide variant
Location: chr20:5176652 (GRCh38)
Gene constraint: LOEUF 0.944 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.70

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

Similar variants

CDS2 p.Met99Leu Uncertain significance ★ ⚠ same residue
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

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-met99thr (accessed [today's date]).

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