Is PDCD4 p.Ser323Phe (c.968C>T) pathogenic?

PDCD4 p.Ser323Phe (c.968C>T) is classified Uncertain significance in PDCD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: ambiguous (0.455); Ultra-rare (popmax 0.0144%, nfe).

How common is PDCD4 p.Ser323Phe (c.968C>T) in the general population?

PDCD4 p.Ser323Phe (c.968C>T) is ultra-rare (popmax 0.0144%, nfe) (gnomAD).

What do computational predictors say about PDCD4 p.Ser323Phe (c.968C>T)?

AlphaMissense predicts ambiguous (score 0.455) — an in-silico prediction, not a clinical call.

PDCD4 p.Ser323Phe

c.968C>T · VCV4830612

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.455 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0144%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.455	ambiguous
REVEL	0.134	moderately benign-leaning
SaProt	LLR -11.29	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 22 kb · p 0.31 · regional, not allelic
Overall
CADD	27.1	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 0.0144% European (non-Finnish) · 169/1,174,516 alleles

Filtering AF 0.0126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0119%

Overall 0.0106% 170/1,607,538 alleles · ultra-rare exomes 167/1,455,414 · genomes 3/152,124 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0144%	6,950
Remaining individualsnot grpmax-eligible	0.00161%	62,246

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.Ser323Phe
Coding: c.968C>T
MANE Select: NM_014456
Type: single nucleotide variant
Location: chr10:110890648 (GRCh38)
Gene constraint: LOEUF 1.671 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 11 PDB

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

Similar variants

PDCD4 p.Ala118Val Uncertain significance ★ ⚠ same type
PDCD4 p.Ala84Thr Uncertain significance ★ ⚠ same type
PDCD4 p.Arg310Cys Uncertain significance ★ ⚠ same type
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-ser323phe (accessed [today's date]).

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