Is PDCD6 p.Arg100Cys (c.298C>T) pathogenic?

PDCD6 p.Arg100Cys (c.298C>T) is classified Uncertain significance in PDCD6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-17). AlphaMissense: likely pathogenic (0.8959); Ultra-rare (popmax 0.0114%, nfe).

How common is PDCD6 p.Arg100Cys (c.298C>T) in the general population?

PDCD6 p.Arg100Cys (c.298C>T) is ultra-rare (popmax 0.0114%, nfe) (gnomAD).

What do computational predictors say about PDCD6 p.Arg100Cys (c.298C>T)?

AlphaMissense predicts likely pathogenic (score 0.8959) — an in-silico prediction, not a clinical call.

PDCD6 p.Arg100Cys

c.298C>T · rs758565797 · VCV2225202

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8959 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0114%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8959	likely pathogenic
REVEL	0.472	indeterminate
SaProt	LLR -12.48	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 7,910 bp · p 0.049 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0114% European (non-Finnish) · 135/1,180,024 alleles

Filtering AF 0.00986% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0092%

Overall 0.0131% 212/1,613,952 alleles · ultra-rare exomes 194/1,461,734 · genomes 18/152,218 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0798%	1,253
Remaining individualsnot grpmax-eligible	0.0208%	4,807
European (non-Finnish)grpmax	0.0114%	8,741
African / African-American	0.00801%	12,490
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,803
East Asian	0.00668%	14,967
South Asian	0.0022%	45,545

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: PDCD6
Protein: p.Arg100Cys
Coding: c.298C>T
MANE Select: NM_013232
dbSNP: rs758565797
Type: single nucleotide variant
Location: chr5:306691 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 90.08 · 10 PDB
Residue 100: the ef-hand 3 domain; an α-helix

Full PDCD6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PDCD6 p.Ala118Thr Uncertain significance ★ ⚠ same type
PDCD6 p.Arg125Trp Uncertain significance ★ ⚠ same type
PDCD6 p.Arg136Gln Uncertain significance ★ ⚠ same type
PDCD6 p.Asn54Lys Uncertain significance ★ ⚠ same type
PDCD6 p.Asn54Ser Uncertain significance ★ ⚠ same type
PDCD6 p.Asp139Gly Uncertain significance ★ ⚠ same type
PDCD6 p.Cys155Phe Uncertain significance ★ ⚠ same type
PDCD6 p.Gln50Arg 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/pdcd6-p-arg100cys (accessed [today's date]).

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