Is NPHP4 p.Pro1055Leu (c.3164C>T) pathogenic?

NPHP4 p.Pro1055Leu (c.3164C>T) is classified Uncertain significance in NPHP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-05-06). AlphaMissense: likely pathogenic (0.6853); Very rare (popmax 0.00179%, nfe).

How common is NPHP4 p.Pro1055Leu (c.3164C>T) in the general population?

NPHP4 p.Pro1055Leu (c.3164C>T) is very rare (popmax 0.00179%, nfe) (gnomAD).

What do computational predictors say about NPHP4 p.Pro1055Leu (c.3164C>T)?

AlphaMissense predicts likely pathogenic (score 0.6853) — an in-silico prediction, not a clinical call.

NPHP4 p.Pro1055Leu

c.3164C>T · rs1398568182 · VCV1302630

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6853 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00179%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6853	likely pathogenic
REVEL	0.654	pathogenic-leaning
SaProt	LLR -14.56	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	28.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00179% European (non-Finnish) · 21/1,172,950 alleles

Filtering AF 0.00115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000976%

Overall 0.0015% 24/1,598,354 alleles · very rare exomes 24/1,445,982 · genomes 0/152,372 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00485%	20,617
European (non-Finnish)grpmax	0.00179%	55,855

Remaining individuals 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: NPHP4
Protein: p.Pro1055Leu
Coding: c.3164C>T
MANE Select: NM_015102
dbSNP: rs1398568182
Type: single nucleotide variant
Location: chr1:5874538 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 1055: the 'sufficient for basal bodies localization' region

Full NPHP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NPHP4 p.Pro1055= Uncertain significance ★ same residue
NPHP4 p.Pro1055Ser Uncertain significance ★ same residue
NPHP4 c.2304+1G>A Pathogenic ★★ same type
NPHP4 c.2611+1G>A Pathogenic/Likely pathogenic ★★ same type
NPHP4 c.2611+1G>C Pathogenic ★★ same type
NPHP4 c.3644+1G>A Pathogenic/Likely pathogenic ★★ same type
NPHP4 c.3644+1G>T Pathogenic/Likely pathogenic ★★ same type
NPHP4 c.517+1G>A Pathogenic/Likely pathogenic ★★ same type

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/nphp4-p-pro1055leu (accessed [today's date]).

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