Is PLCD1 p.Cys339Phe (c.1016G>T) pathogenic?

PLCD1 p.Cys339Phe (c.1016G>T) is classified Uncertain significance in PLCD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-03). AlphaMissense: likely pathogenic (0.9004); Very rare (popmax 6.19e-05%); Associated with nonsyndromic congenital nail disorder 3.

What condition is associated with PLCD1 p.Cys339Phe (c.1016G>T)?

PLCD1 p.Cys339Phe (c.1016G>T) is associated with nonsyndromic congenital nail disorder 3 (ClinVar).

How common is PLCD1 p.Cys339Phe (c.1016G>T) in the general population?

PLCD1 p.Cys339Phe (c.1016G>T) is very rare (popmax 6.19e-05%) (gnomAD).

What do computational predictors say about PLCD1 p.Cys339Phe (c.1016G>T)?

AlphaMissense predicts likely pathogenic (score 0.9004) — an in-silico prediction, not a clinical call.

PLCD1 p.Cys339Phe

c.1016G>T · rs2125544142 · VCV1333358

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9004 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.19e-05%)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nonsyndromic congenital nail disorder 3

Computational evidence

Protein change
AlphaMissense	0.9004	likely pathogenic
REVEL	0.695	pathogenic-leaning
SaProt	LLR -12.95	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 22 kb · p 2.1e-05 · regional, not allelic
Overall
CADD	26.3	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 6.19e-05%

Overall 6.19e-05% 1/1,614,232 alleles · very rare exomes 1/1,461,892 · genomes 0/152,340 · 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: PLCD1
Protein: p.Cys339Phe
Coding: c.1016G>T
MANE Select: NM_006225
dbSNP: rs2125544142
Type: single nucleotide variant
Location: chr3:38010252 (GRCh38)
Gene constraint: LOEUF 0.954 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.31
Residue 339: the pi-plc x-box domain

Full PLCD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nonsyndromic congenital nail disorder 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PLCD1 p.Arg530Ter Pathogenic/Likely pathogenic ★★ same condition
PLCD1 p.Arg138His Uncertain significance ★★ ⚠ same condition
PLCD1 p.Arg476His Uncertain significance ★★ ⚠ same condition
PLCD1 p.Arg60Gln Uncertain significance ★★ ⚠ same condition
PLCD1 p.Gln533Ter Likely pathogenic ★ same condition
PLCD1 p.Gln622Ter Likely pathogenic ★ same condition
PLCD1 c.1137+5G>C Uncertain significance ★ same condition
PLCD1 p.Ala402Val Uncertain significance ★ ⚠ same condition

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/plcd1-p-cys339phe (accessed [today's date]).

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