Is PKHD1 p.Pro677Ser (c.2029C>T) pathogenic?

PKHD1 p.Pro677Ser (c.2029C>T) is classified Uncertain significance in PKHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-07). AlphaMissense: likely benign (0.0749); Very rare (popmax 0.000169%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PKHD1 p.Pro677Ser (c.2029C>T)?

PKHD1 p.Pro677Ser (c.2029C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PKHD1 p.Pro677Ser (c.2029C>T) in the general population?

PKHD1 p.Pro677Ser (c.2029C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about PKHD1 p.Pro677Ser (c.2029C>T)?

AlphaMissense predicts likely benign (score 0.0749) — an in-silico prediction, not a clinical call.

PKHD1 p.Pro677Ser

c.2029C>T · VCV3933113

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0749 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0749	likely benign
REVEL	0.138	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.41	GERP -0.68
Regional constraint	o/e 0.97	unconstrained · MANE · 466 kb · p 0.074 · regional, not allelic
Overall
CADD	0.816	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 0.000169% European (non-Finnish) · 2/1,180,030 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,866 alleles · very rare

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.Pro677Ser
Coding: c.2029C>T
MANE Select: NM_138694
Type: single nucleotide variant
Location: chr6:52053187 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Residue 677: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PKHD1 p.Trp2690Arg Pathogenic/Likely pathogenic ★★ same condition
PKHD1 c.2141-3T>C Uncertain significance ★★ same condition
PKHD1 c.880+5C>T Uncertain significance ★★ same condition
PKHD1 p.Ala1455Thr Uncertain significance ★★ ⚠ same condition
PKHD1 p.Ala182Thr Uncertain significance ★★ same condition
PKHD1 p.Ala2832Ser Uncertain significance ★★ same condition
PKHD1 p.Arg2611Cys Uncertain significance ★★ ⚠ same condition
PKHD1 p.Arg2891His Uncertain significance ★★ 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-pro677ser (accessed [today's date]).

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