Is PRKD1 p.Ser549Phe (c.1646C>T) pathogenic?

PRKD1 p.Ser549Phe (c.1646C>T) is classified Uncertain significance in PRKD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-28). AlphaMissense: likely benign (0.1116); Very rare (popmax 0.000847%, nfe).

How common is PRKD1 p.Ser549Phe (c.1646C>T) in the general population?

PRKD1 p.Ser549Phe (c.1646C>T) is very rare (popmax 0.000847%, nfe) (gnomAD).

What do computational predictors say about PRKD1 p.Ser549Phe (c.1646C>T)?

AlphaMissense predicts likely benign (score 0.1116) — an in-silico prediction, not a clinical call.

PRKD1 p.Ser549Phe

c.1646C>T · VCV3938176

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1116 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000847%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1116	likely benign
REVEL	0.195	benign-leaning
SaProt	LLR -8.33	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 86 kb · p 2.8e-05 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000847% European (non-Finnish) · 10/1,179,982 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.00062% 10/1,614,080 alleles · very rare exomes 10/1,461,818 · genomes 0/152,262 · 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: PRKD1
Protein: p.Ser549Phe
Coding: c.1646C>T
MANE Select: NM_002742
Type: single nucleotide variant
Location: chr14:29630768 (GRCh38)
Gene constraint: LOEUF 0.762 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.99

Full PRKD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PRKD1 p.Ala529Thr Uncertain significance ★★ ⚠ same type
PRKD1 p.Arg201Trp Uncertain significance ★★ same type
PRKD1 p.Arg203Lys Uncertain significance ★★ ⚠ same type
PRKD1 p.Arg740Gln Uncertain significance ★★ ⚠ same type
PRKD1 p.Asn498Ser Uncertain significance ★★ ⚠ same type
PRKD1 p.Gln115His Uncertain significance ★★ ⚠ same type
PRKD1 p.Gly486Arg Uncertain significance ★★ ⚠ same type
PRKD1 p.Met424Val 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/prkd1-p-ser549phe (accessed [today's date]).

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