Is NPHP4 p.Phe91Leu (c.271T>C) pathogenic?

NPHP4 p.Phe91Leu (c.271T>C) is classified Conflicting classifications of pathogenicity in NPHP4 (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-01-15). AlphaMissense: likely pathogenic (0.8817); Rare (popmax 0.193%, nfe); Associated with nephronophthisis.

What condition is associated with NPHP4 p.Phe91Leu (c.271T>C)?

NPHP4 p.Phe91Leu (c.271T>C) is associated with nephronophthisis, nephronophthisis 4, Senior-Loken syndrome 4 (ClinVar).

How common is NPHP4 p.Phe91Leu (c.271T>C) in the general population?

NPHP4 p.Phe91Leu (c.271T>C) is rare (popmax 0.193%, nfe) (gnomAD).

How is Nephronophthisis inherited?

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

What do computational predictors say about NPHP4 p.Phe91Leu (c.271T>C)?

AlphaMissense predicts likely pathogenic (score 0.8817) — an in-silico prediction, not a clinical call.

NPHP4 p.Phe91Leu

c.271T>C · rs201065230 · VCV196471

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 13 submitters

AlphaMissense

likely pathogenic

0.8817 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.193%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.8817	likely pathogenic · top 7% in NPHP4
REVEL	0.669	pathogenic-leaning
SaProt	LLR -7.83	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 0.53, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	17.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.193% European (non-Finnish) · 2,275/1,176,926 alleles

Filtering AF 0.187% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.184%

Overall 0.149% 2,390/1,606,598 alleles · rare exomes 2,230/1,454,526 · genomes 160/152,072 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.193%	517
Remaining individualsnot grpmax-eligible	0.0852%	1,174
Finnishnot grpmax-eligible	0.0541%	1,847
African / African-American	0.0321%	3,113
Admixed American	0.00678%	14,751

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.Phe91Leu
Coding: c.271T>C
MANE Select: NM_015102
dbSNP: rs201065230
Type: single nucleotide variant
Location: chr1:5978278 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 91: a UniProt-annotated variant site (in slsn4; also found in a patient with cardiac laterality defects; impairs localization to the ciliary transition zone)

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

Disease context

nephronophthisis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis 4 Senior-Loken syndrome 4

For Nephronophthisis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Finland)

Similar variants

NPHP4 c.2304+1G>A Pathogenic ★★ same condition
NPHP4 c.2611+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.2611+1G>C Pathogenic ★★ same condition
NPHP4 c.3644+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.3644+1G>T Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.517+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.518-2A>G Likely pathogenic ★★ same condition
NPHP4 c.992+2T>C 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/nphp4-p-phe91leu (accessed [today's date]).

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