Is PKHD1 p.Pro676Arg (c.2027C>G) pathogenic?

PKHD1 p.Pro676Arg (c.2027C>G) is classified Benign/Likely benign in PKHD1 (ClinVar, Multiple submitters, 16 submitters; last evaluated 2026-05-01). AlphaMissense: likely benign (0.0897); Low-frequency (popmax 2.29%, afr); Associated with polycystic kidney disease 4.

What condition is associated with PKHD1 p.Pro676Arg (c.2027C>G)?

PKHD1 p.Pro676Arg (c.2027C>G) is associated with polycystic kidney disease 4, autosomal recessive polycystic kidney disease (ClinVar).

How common is PKHD1 p.Pro676Arg (c.2027C>G) in the general population?

PKHD1 p.Pro676Arg (c.2027C>G) is low-frequency (popmax 2.29%, afr) (gnomAD).

How is Autosomal recessive polycystic kidney disease inherited?

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

What do computational predictors say about PKHD1 p.Pro676Arg (c.2027C>G)?

AlphaMissense predicts likely benign (score 0.0897) — an in-silico prediction, not a clinical call.

PKHD1 p.Pro676Arg

c.2027C>G · rs115045643 · VCV96383

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 16 submitters

AlphaMissense

likely benign

0.0897 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.29%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

polycystic kidney disease 4

Computational evidence

Protein change
AlphaMissense	0.0897	likely benign
REVEL	0.205	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.6	GERP -4.3
Regional constraint	o/e 0.97	unconstrained · MANE · 466 kb · p 0.074 · regional, not allelic
Overall
CADD	0.777	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.29% African / African-American · 1,722/75,048 alleles

Filtering AF 2.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.17%

Overall 0.127% 2,055/1,614,190 alleles · low-frequency exomes 1,034/1,461,856 · genomes 1,021/152,334 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.29%	44
Middle Eastern	0.363%	276
Admixed American	0.195%	513
Remaining individualsnot grpmax-eligible	0.192%	521
South Asian	0.00768%	13,013
European (non-Finnish)	0.00568%	17,612

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.Pro676Arg
Coding: c.2027C>G
MANE Select: NM_138694
dbSNP: rs115045643
Type: single nucleotide variant
Location: chr6:52053189 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Residue 676: a UniProt-annotated variant site (found in a patient affected by polycystic liver disease; uncertain significance)

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

Disease context

polycystic kidney disease 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive polycystic kidney disease

For Autosomal recessive polycystic kidney disease (Orphanet):

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

Similar variants

PKHD1 p.Pro676His Uncertain significance ★ same residue
PKHD1 p.Pro676Ser 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
PKHD1 c.11666-2A>G 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-pro676arg (accessed [today's date]).

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