Is PKHD1 p.Val419= (c.1257C>T) pathogenic?

PKHD1 p.Val419= (c.1257C>T) is classified Conflicting classifications of pathogenicity in PKHD1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-13). Ultra-rare (popmax 0.066%, mid); Associated with autosomal recessive polycystic kidney disease.

What condition is associated with PKHD1 p.Val419= (c.1257C>T)?

PKHD1 p.Val419= (c.1257C>T) is associated with autosomal recessive polycystic kidney disease (ClinVar).

How common is PKHD1 p.Val419= (c.1257C>T) in the general population?

PKHD1 p.Val419= (c.1257C>T) is ultra-rare (popmax 0.066%, mid) (gnomAD).

How is Autosomal recessive polycystic kidney disease inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

PKHD1 p.Val419=

c.1257C>T · rs374650666 · VCV593613

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.066%, mid)

Conditions

autosomal recessive polycystic kidney disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.29	GERP -4.4
Overall
CADD	1.634	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.066% Middle Eastern · 4/6,062 alleles

Filtering AF 0.035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0296%

Overall 0.0196% 316/1,614,060 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.233%	429
Middle Easterngrpmax	0.066%	1,516
East Asian	0.0512%	1,952
Ashkenazi Jewishnot grpmax-eligible	0.0507%	1,974
Remaining individualsnot grpmax-eligible	0.0256%	3,906
South Asian	0.0121%	8,280
European (non-Finnish)	0.00797%	12,553
Admixed American	0.005%	20,005
African / African-American	0.00133%	75,030

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: PKHD1
Protein: p.Val419=
Coding: c.1257C>T
MANE Select: NM_138694
dbSNP: rs374650666
Type: single nucleotide variant
Location: chr6:52058578 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Residue 419: the pa14 domain

Full PKHD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive polycystic kidney disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive polycystic kidney disease (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 100 000 (Germany)

Similar variants

PKHD1 p.Val419Ala Uncertain significance ★★ ⚠ same residue
PKHD1 p.Val419Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
PKHD1 p.Val419Phe Uncertain significance ★ ⚠ same residue
PKHD1 c.11174+2T>C Likely pathogenic ★★ same condition
PKHD1 c.11310+1G>C Pathogenic/Likely pathogenic ★★ same condition
PKHD1 c.11398+2T>C Pathogenic/Likely pathogenic ★★ same condition
PKHD1 c.11507-1G>A Likely pathogenic ★★ same condition
PKHD1 c.11665+1G>A Pathogenic/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/pkhd1-p-val419 (accessed [today's date]).

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