Is PDCD4 p.Leu340Pro (c.1019T>C) pathogenic?

PDCD4 p.Leu340Pro (c.1019T>C) is classified Uncertain significance in PDCD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-13). AlphaMissense: likely pathogenic (0.9771); Very rare (popmax 0.000171%, nfe).

How common is PDCD4 p.Leu340Pro (c.1019T>C) in the general population?

PDCD4 p.Leu340Pro (c.1019T>C) is very rare (popmax 0.000171%, nfe) (gnomAD).

What do computational predictors say about PDCD4 p.Leu340Pro (c.1019T>C)?

AlphaMissense predicts likely pathogenic (score 0.9771) — an in-silico prediction, not a clinical call.

PDCD4 p.Leu340Pro

c.1019T>C · rs770737625 · VCV3210577

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9771 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000171%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9771	likely pathogenic
REVEL	0.325	indeterminate
SaProt	LLR -11.29	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 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 22 kb · p 0.31 · regional, not allelic
Overall
CADD	24.5	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 0.000171% European (non-Finnish) · 2/1,172,940 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000125% 2/1,605,934 alleles · very rare exomes 2/1,453,684 · genomes 0/152,250 · joint denominator

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.Leu340Pro
Coding: c.1019T>C
MANE Select: NM_014456
dbSNP: rs770737625
Type: single nucleotide variant
Location: chr10:110894119 (GRCh38)
Gene constraint: LOEUF 1.671 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 11 PDB
Residue 340: the mi 2 domain; an α-helix

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
PDCD4 p.Asn410Ser Uncertain significance ★ ⚠ same type
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-leu340pro (accessed [today's date]).

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