Is CDS2 p.Val116Ile (c.346G>A) pathogenic?

CDS2 p.Val116Ile (c.346G>A) is classified Uncertain significance in CDS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). AlphaMissense: likely benign (0.2036); Very rare (popmax 0.00988%, sas).

How common is CDS2 p.Val116Ile (c.346G>A) in the general population?

CDS2 p.Val116Ile (c.346G>A) is very rare (popmax 0.00988%, sas) (gnomAD).

What do computational predictors say about CDS2 p.Val116Ile (c.346G>A)?

AlphaMissense predicts likely benign (score 0.2036) — an in-silico prediction, not a clinical call.

CDS2 p.Val116Ile

c.346G>A · rs576280057 · VCV2510858

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2036 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00988%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2036	likely benign
REVEL	0.247	benign-leaning
SaProt	LLR -6.83	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.45	unconstrained · MANE · 9,113 bp · p 2.1e-14 · regional, not allelic
Overall
CADD	31.0	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 0.00988% South Asian · 9/91,086 alleles

Filtering AF 0.00514% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00375%

Overall 0.00124% 20/1,614,098 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00988%	10,121
East Asian	0.00668%	14,964
Remaining individualsnot grpmax-eligible	0.0048%	20,836
European (non-Finnish)	0.000424%	235,993

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.Val116Ile
Coding: c.346G>A
MANE Select: NM_003818
dbSNP: rs576280057
Type: single nucleotide variant
Location: chr20:5176702 (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.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-val116ile (accessed [today's date]).

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