Is PKDCC p.Ser109Pro (c.325T>C) pathogenic?

PKDCC p.Ser109Pro (c.325T>C) is classified Benign in PKDCC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0454); Common (popmax 40.9%, eas) — too common for a highly-penetrant pathogenic allele; Associated with rhizomelic limb shortening with dysmorphic features.

What condition is associated with PKDCC p.Ser109Pro (c.325T>C)?

PKDCC p.Ser109Pro (c.325T>C) is associated with rhizomelic limb shortening with dysmorphic features (ClinVar).

What do computational predictors say about PKDCC p.Ser109Pro (c.325T>C)?

AlphaMissense predicts likely benign (score 0.0454) — an in-silico prediction, not a clinical call.

PKDCC p.Ser109Pro

Q: How common is PKDCC p.Ser109Pro (c.325T>C) in the general population?

PKDCC p.Ser109Pro (c.325T>C) is common (popmax 40.9%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.325T>C · rs187184761 · VCV1327044

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0454 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 40.9%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

rhizomelic limb shortening with dysmorphic features

Computational evidence

Protein change
AlphaMissense	0.0454	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -4.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Regional constraint	o/e 1.10	unconstrained · MANE · 9,485 bp · p 0.012 · regional, not allelic
Overall
CADD	11.56	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 40.9% East Asian · 10,615/25,930 alleles

Filtering AF 40.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 40%

Overall 13.7% 164,251/1,202,592 alleles · common exomes 143,987/1,054,852 · genomes 20,264/147,740 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	40.9%	2
Admixed American	35%	3
South Asian	17.6%	6
Remaining individualsnot grpmax-eligible	13.9%	7
European (non-Finnish)	13.2%	8
Middle Eastern	7.78%	13
Ashkenazi Jewishnot grpmax-eligible	7.74%	13
Amishnot grpmax-eligible	7.65%	13
African / African-American	5.96%	17
Finnishnot grpmax-eligible	5.87%	17

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: PKDCC
Protein: p.Ser109Pro
Coding: c.325T>C
MANE Select: NM_138370
dbSNP: rs187184761
Type: single nucleotide variant
Location: chr2:42048524 (GRCh38)
Gene constraint: LOEUF 1.15 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.96
Residue 109: the 'disordered' region

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

Disease context

rhizomelic limb shortening with dysmorphic features — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PKDCC p.Leu262Arg Pathogenic/Likely pathogenic ★★ same condition
PKDCC c.640-2A>T Likely pathogenic ★ same condition
PKDCC p.Arg252Ter Pathogenic ★ same condition
PKDCC p.Trp376Ter Likely pathogenic ★ same condition
PKDCC p.Tyr217Ter Pathogenic ★ same condition
PKDCC p.Leu314fs Pathogenic ★ same condition
PKDCC p.Leu97fs Likely pathogenic ★ same condition
PKDCC p.Pro77fs Likely pathogenic ★ 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/pkdcc-p-ser109pro (accessed [today's date]).

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