Is PDCD4 p.Ser76Leu (c.227C>T) pathogenic?

PDCD4 p.Ser76Leu (c.227C>T) is classified Uncertain significance in PDCD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: ambiguous (0.3756); Very rare (popmax 0.00446%, eas).

How common is PDCD4 p.Ser76Leu (c.227C>T) in the general population?

PDCD4 p.Ser76Leu (c.227C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about PDCD4 p.Ser76Leu (c.227C>T)?

AlphaMissense predicts ambiguous (score 0.3756) — an in-silico prediction, not a clinical call.

PDCD4 p.Ser76Leu

c.227C>T · rs763092811 · VCV2266469

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3756 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3756	ambiguous
REVEL	0.201	benign-leaning
SaProt	LLR -7.83	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 22 kb · p 0.31 · regional, not allelic
Overall
CADD	24.3	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 0.00446% East Asian · 2/44,886 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000434% 7/1,614,188 alleles · very rare exomes 7/1,461,874 · genomes 0/152,314 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,443
Remaining individualsnot grpmax-eligible	0.0016%	62,504
European (non-Finnish)	0.000339%	295,009

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: PDCD4
Protein: p.Ser76Leu
Coding: c.227C>T
MANE Select: NM_014456
dbSNP: rs763092811
Type: single nucleotide variant
Location: chr10:110881416 (GRCh38)
Gene constraint: LOEUF 1.671 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 11 PDB
Residue 76: a modified residue (phosphoserine); the 'disordered' region

Full PDCD4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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PDCD4 p.Arg428Trp Uncertain significance ★ ⚠ same type
PDCD4 p.Arg61Thr Uncertain significance ★ ⚠ same type
PDCD4 p.Arg69Trp Uncertain significance ★ ⚠ same type
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PDCD4 p.Asp144His 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/pdcd4-p-ser76leu (accessed [today's date]).

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