Is NPHP4 p.Thr477= (c.1431G>A) pathogenic?

NPHP4 p.Thr477= (c.1431G>A) is classified Likely benign in NPHP4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-21). Rare (popmax 0.1%, afr); Associated with Inborn genetic diseases.

What condition is associated with NPHP4 p.Thr477= (c.1431G>A)?

NPHP4 p.Thr477= (c.1431G>A) is associated with Inborn genetic diseases, nephronophthisis 4, Senior-Loken syndrome 4 (ClinVar).

How common is NPHP4 p.Thr477= (c.1431G>A) in the general population?

NPHP4 p.Thr477= (c.1431G>A) is rare (popmax 0.1%, afr) (gnomAD).

NPHP4 p.Thr477=

c.1431G>A · rs200183657 · VCV700098

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.1%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -9.1	GERP -3.7
Overall
CADD	2.334	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.1% African / African-American · 75/74,978 alleles

Filtering AF 0.0818% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0751%

Overall 0.00776% 125/1,610,576 alleles · rare exomes 76/1,458,328 · genomes 49/152,248 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.1%	1,000
Middle Eastern	0.0496%	2,015
Remaining individualsnot grpmax-eligible	0.016%	6,232
Admixed American	0.0117%	8,563
European (non-Finnish)	0.00229%	43,597
East Asian	0.00223%	44,754
South Asian	0.0022%	45,500

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.Thr477=
Coding: c.1431G>A
MANE Select: NM_015102
dbSNP: rs200183657
Type: single nucleotide variant
Location: chr1:5927659 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 477: the 'disordered' 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 4 Senior-Loken syndrome 4 nephronophthisis

Similar variants

NPHP4 p.Thr477Met 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.517+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.518-2A>G 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-thr477 (accessed [today's date]).

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