Is PDCD2L p.Ser69Phe (c.206C>T) pathogenic?

PDCD2L p.Ser69Phe (c.206C>T) is classified Uncertain significance in PDCD2L (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-24). AlphaMissense: ambiguous (0.4365); Ultra-rare (popmax 0.0506%, sas).

How common is PDCD2L p.Ser69Phe (c.206C>T) in the general population?

PDCD2L p.Ser69Phe (c.206C>T) is ultra-rare (popmax 0.0506%, sas) (gnomAD).

What do computational predictors say about PDCD2L p.Ser69Phe (c.206C>T)?

AlphaMissense predicts ambiguous (score 0.4365) — an in-silico prediction, not a clinical call.

PDCD2L p.Ser69Phe

c.206C>T · rs140108926 · VCV2231376

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4365 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0506%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4365	ambiguous
REVEL	0.237	benign-leaning
SaProt	LLR -12.80	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.4, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 22 kb · p 0.44 · regional, not allelic
Overall
CADD	27.9	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 0.0506% South Asian · 46/90,986 alleles

Filtering AF 0.0389% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0348%

Overall 0.00788% 127/1,611,796 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0506%	1,978
Middle Eastern	0.0165%	6,058
Remaining individualsnot grpmax-eligible	0.016%	6,241
African / African-American	0.0147%	6,823
European (non-Finnish)	0.00492%	20,340
East Asian	0.00223%	44,844

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: PDCD2L
Protein: p.Ser69Phe
Coding: c.206C>T
MANE Select: NM_032346
dbSNP: rs140108926
Type: single nucleotide variant
Location: chr19:34404746 (GRCh38)
Gene constraint: LOEUF 1.374 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.93

Full PDCD2L gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PDCD2L p.Ala111Val Uncertain significance ★ ⚠ same type
PDCD2L p.Ala174Thr Uncertain significance ★ ⚠ same type
PDCD2L p.Ala175Val Uncertain significance ★ ⚠ same type
PDCD2L p.Ala258Val Uncertain significance ★ ⚠ same type
PDCD2L p.Ala2Val Uncertain significance ★ ⚠ same type
PDCD2L p.Ala38Ser Uncertain significance ★ ⚠ same type
PDCD2L p.Ala44Ser Uncertain significance ★ ⚠ same type
PDCD2L p.Ala81Thr 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/pdcd2l-p-ser69phe (accessed [today's date]).

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