Is PKD1 p.Leu4026Val (c.12076C>G) pathogenic?

PKD1 p.Leu4026Val (c.12076C>G) is classified Uncertain significance in PKD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-31). AlphaMissense: likely benign (0.144); Very rare (popmax 0.00195%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PKD1 p.Leu4026Val (c.12076C>G)?

PKD1 p.Leu4026Val (c.12076C>G) is associated with Inborn genetic diseases (ClinVar).

How common is PKD1 p.Leu4026Val (c.12076C>G) in the general population?

PKD1 p.Leu4026Val (c.12076C>G) is very rare (popmax 0.00195%, nfe) (gnomAD).

What do computational predictors say about PKD1 p.Leu4026Val (c.12076C>G)?

AlphaMissense predicts likely benign (score 0.144) — an in-silico prediction, not a clinical call.

PKD1 p.Leu4026Val

c.12076C>G · rs938492146 · VCV2274895

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.144 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00195%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.144	likely benign
REVEL	0.367	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP -0.88, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 11 kb · p 1.9e-30 · regional, not allelic
Overall
CADD	20.8	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 0.00195% European (non-Finnish) · 23/1,179,976 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00149% 24/1,612,532 alleles · very rare exomes 22/1,460,332 · genomes 2/152,200 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00195%	51,303
Remaining individualsnot grpmax-eligible	0.0016%	62,462

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: PKD1
Protein: p.Leu4026Val
Coding: c.12076C>G
MANE Select: NM_001009944
dbSNP: rs938492146
Type: single nucleotide variant
Location: chr16:2090736 (GRCh38)
Gene constraint: LOEUF 0.364 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 4026: an α-helix

Full PKD1 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

PKD1 p.Leu4026Arg Uncertain significance ★ ⚠ same residue
PKD1 p.Leu4026= Likely benign ★ same residue
PKD1 c.11017-10C>A Pathogenic/Likely pathogenic ★★ same condition
PKD1 c.1385+1G>C Pathogenic/Likely pathogenic ★★ same condition
PKD1 c.3295+1G>C Pathogenic/Likely pathogenic ★★ same condition
PKD1 p.Arg138Ter Pathogenic ★★ same condition
PKD1 p.Arg4021Ter Pathogenic ★★ same condition
PKD1 p.Gln1172Ter 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/pkd1-p-leu4026val (accessed [today's date]).

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