Is NPHP4 p.Val1241Ile (c.3721G>A) pathogenic?

NPHP4 p.Val1241Ile (c.3721G>A) is classified Uncertain significance in NPHP4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-22). AlphaMissense: likely benign (0.08); Very rare (popmax 0.00373%, nfe); Associated with Inborn genetic diseases.

What condition is associated with NPHP4 p.Val1241Ile (c.3721G>A)?

NPHP4 p.Val1241Ile (c.3721G>A) is associated with Inborn genetic diseases, nephronophthisis (ClinVar).

How common is NPHP4 p.Val1241Ile (c.3721G>A) in the general population?

NPHP4 p.Val1241Ile (c.3721G>A) is very rare (popmax 0.00373%, nfe) (gnomAD).

What do computational predictors say about NPHP4 p.Val1241Ile (c.3721G>A)?

AlphaMissense predicts likely benign (score 0.08) — an in-silico prediction, not a clinical call.

NPHP4 p.Val1241Ile

c.3721G>A · rs535789951 · VCV955373

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.08 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00373%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.08	likely benign
REVEL	0.174	moderately benign-leaning
SaProt	LLR -7.83	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.43 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1	GERP -3.6
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	6.49	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 0.00373% European (non-Finnish) · 44/1,178,658 alleles

Filtering AF 0.00283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00252%

Overall 0.00323% 52/1,611,346 alleles · very rare exomes 49/1,459,134 · genomes 3/152,212 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00373%	26,788
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,568
Admixed American	0.00334%	29,950
African / African-American	0.00267%	37,458
South Asian	0.0022%	45,476
Finnishnot grpmax-eligible	0.00158%	63,202

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.Val1241Ile
Coding: c.3721G>A
MANE Select: NM_015102
dbSNP: rs535789951
Type: single nucleotide variant
Location: chr1:5865197 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 1241: the 'sufficient for basal bodies localization' region

Full NPHP4 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

Also linked: nephronophthisis

Similar variants

NPHP4 p.Val1241= Conflicting classifications of pathogenicity ★ same residue
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.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-val1241ile (accessed [today's date]).

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