Is NPHP4 p.Val944Ile (c.2830G>A) pathogenic?

NPHP4 p.Val944Ile (c.2830G>A) is classified Uncertain significance in NPHP4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-12-09). AlphaMissense: likely benign (0.0764); Ultra-rare (popmax 0.0268%, eas); Associated with Inborn genetic diseases.

What condition is associated with NPHP4 p.Val944Ile (c.2830G>A)?

NPHP4 p.Val944Ile (c.2830G>A) is associated with Inborn genetic diseases, nephronophthisis (ClinVar).

How common is NPHP4 p.Val944Ile (c.2830G>A) in the general population?

NPHP4 p.Val944Ile (c.2830G>A) is ultra-rare (popmax 0.0268%, eas) (gnomAD).

What do computational predictors say about NPHP4 p.Val944Ile (c.2830G>A)?

AlphaMissense predicts likely benign (score 0.0764) — an in-silico prediction, not a clinical call.

NPHP4 p.Val944Ile

c.2830G>A · rs188262700 · VCV502514

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0764 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0268%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0764	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -6.35	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.6	GERP -3.2
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	1.022	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 0.0268% East Asian · 12/44,722 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.00986% 158/1,602,178 alleles · ultra-rare exomes 141/1,449,866 · genomes 17/152,312 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0268%	3,727
Admixed American	0.0185%	5,412
Middle Eastern	0.0167%	5,996
South Asian	0.0133%	7,535
Remaining individualsnot grpmax-eligible	0.0112%	8,903
European (non-Finnish)	0.00934%	10,710
African / African-American	0.00534%	18,742
Finnishnot grpmax-eligible	0.00179%	55,716

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.Val944Ile
Coding: c.2830G>A
MANE Select: NM_015102
dbSNP: rs188262700
Type: single nucleotide variant
Location: chr1:5875088 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 944: 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 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
NPHP4 p.Arg1109Ter Pathogenic/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-val944ile (accessed [today's date]).

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