Is NPHP4 p.Ala1110Val (c.3329C>T) pathogenic?

NPHP4 p.Ala1110Val (c.3329C>T) is classified Conflicting classifications of pathogenicity in NPHP4 (ClinVar, Conflicting submitters, 17 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0887); Rare (popmax 0.683%, nfe); Associated with kidney disorder.

What condition is associated with NPHP4 p.Ala1110Val (c.3329C>T)?

NPHP4 p.Ala1110Val (c.3329C>T) is associated with kidney disorder, nephronophthisis 4, Senior-Loken syndrome 4 (ClinVar).

How common is NPHP4 p.Ala1110Val (c.3329C>T) in the general population?

NPHP4 p.Ala1110Val (c.3329C>T) is rare (popmax 0.683%, nfe) (gnomAD).

What do computational predictors say about NPHP4 p.Ala1110Val (c.3329C>T)?

AlphaMissense predicts likely benign (score 0.0887) — an in-silico prediction, not a clinical call.

NPHP4 p.Ala1110Val

c.3329C>T · rs139767853 · VCV95682

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 17 submitters

AlphaMissense

likely benign

0.0887 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.683%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

kidney disorder

Computational evidence

Protein change
AlphaMissense	0.0887	likely benign
REVEL	0.32	indeterminate
SaProt	LLR -5.39	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.27	GERP -3.8
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	0.28	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 0.683% European (non-Finnish) · 8,055/1,179,868 alleles

Filtering AF 0.67% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.665%

Overall 0.548% 8,844/1,613,652 alleles · rare exomes 8,292/1,461,350 · genomes 552/152,302 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.683%	146
Remaining individualsnot grpmax-eligible	0.387%	258
Admixed American	0.31%	323
Middle Eastern	0.282%	355
Ashkenazi Jewishnot grpmax-eligible	0.27%	370
Finnishnot grpmax-eligible	0.133%	750
African / African-American	0.132%	758
South Asian	0.0856%	1,168
East Asian	0.00446%	22,434

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.Ala1110Val
Coding: c.3329C>T
MANE Select: NM_015102
dbSNP: rs139767853
Type: single nucleotide variant
Location: chr1:5867883 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 1110: the 'sufficient for basal bodies localization' region; a UniProt-annotated variant site (found in a patient with cardiac laterality defects; uncertain significance)

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

Disease context

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

Also linked: nephronophthisis 4 Senior-Loken syndrome 4 nephronophthisis

Similar variants

NPHP4 p.Ala1110= Likely benign ★★ same residue
NPHP4 p.Ala1110Thr Uncertain significance ★ ⚠ 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.517+1G>A 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-ala1110val (accessed [today's date]).

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