Is PLCD1 p.Arg211Trp (c.631C>T) pathogenic?

PLCD1 p.Arg211Trp (c.631C>T) is classified Uncertain significance in PLCD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-10-28). AlphaMissense: likely pathogenic (0.7926); Very rare (popmax 0.00127%, nfe); Associated with Primary degenerative dementia of the Alzheimer type, presenile onset.

What condition is associated with PLCD1 p.Arg211Trp (c.631C>T)?

PLCD1 p.Arg211Trp (c.631C>T) is associated with Primary degenerative dementia of the Alzheimer type, presenile onset (ClinVar).

How common is PLCD1 p.Arg211Trp (c.631C>T) in the general population?

PLCD1 p.Arg211Trp (c.631C>T) is very rare (popmax 0.00127%, nfe) (gnomAD).

What do computational predictors say about PLCD1 p.Arg211Trp (c.631C>T)?

AlphaMissense predicts likely pathogenic (score 0.7926) — an in-silico prediction, not a clinical call.

PLCD1 p.Arg211Trp

c.631C>T · rs752156828 · VCV870546

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7926 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Primary degenerative dementia of the Alzheimer type, presenile onset

Computational evidence

Protein change
AlphaMissense	0.7926	likely pathogenic
REVEL	0.544	indeterminate
SaProt	LLR -15.12	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.8	GERP -2.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 22 kb · p 2.1e-05 · regional, not allelic
Overall
CADD	25.9	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 0.00127% European (non-Finnish) · 15/1,180,028 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00093% 15/1,613,330 alleles · very rare exomes 15/1,460,968 · genomes 0/152,362 · 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.Arg211Trp
Coding: c.631C>T
MANE Select: NM_006225
dbSNP: rs752156828
Type: single nucleotide variant
Location: chr3:38011373 (GRCh38)
Gene constraint: LOEUF 0.954 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.31
Residue 211: the ef-hand 2 domain

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

Disease context

Primary degenerative dementia of the Alzheimer type, presenile onset — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PLCD1 p.Arg211Gln Uncertain significance ★ ⚠ same residue
PLCD1 p.Arg530Ter Pathogenic/Likely pathogenic ★★ same type
PLCD1 p.Arg138His Uncertain significance ★★ ⚠ same type
PLCD1 p.Arg476His Uncertain significance ★★ ⚠ same type
PLCD1 p.Arg60Gln Uncertain significance ★★ ⚠ same type
PLCD1 p.Pro417Arg Uncertain significance ★★ ⚠ same type
PLCD1 p.Ser650Ala Uncertain significance ★★ ⚠ same type
PLCD1 c.1607-42C>T Benign ★★ 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/plcd1-p-arg211trp (accessed [today's date]).

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