Is NPHP3 p.Ala1112= (c.3336T>C) pathogenic?

NPHP3 p.Ala1112= (c.3336T>C) is classified Conflicting classifications of pathogenicity in NPHP3 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-08-28). Ultra-rare (popmax 0.064%, afr); Associated with nephronophthisis.

What condition is associated with NPHP3 p.Ala1112= (c.3336T>C)?

NPHP3 p.Ala1112= (c.3336T>C) is associated with nephronophthisis (ClinVar).

How common is NPHP3 p.Ala1112= (c.3336T>C) in the general population?

NPHP3 p.Ala1112= (c.3336T>C) is ultra-rare (popmax 0.064%, afr) (gnomAD).

How is Nephronophthisis inherited?

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

NPHP3 p.Ala1112=

c.3336T>C · rs188431787 · VCV497618

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.064%, afr)

Conditions

nephronophthisis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.23	GERP 0.67, phastCons 0.4
Overall
CADD	8.199	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.064% African / African-American · 48/75,054 alleles

Filtering AF 0.0495% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0444%

Overall 0.00446% 72/1,613,194 alleles · ultra-rare exomes 42/1,460,846 · genomes 30/152,348 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.064%	1,564
Remaining individualsnot grpmax-eligible	0.0176%	5,682
Admixed American	0.0167%	6,002
South Asian	0.0022%	45,538
European (non-Finnish)	8.47e-05%	1,179,958

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: NPHP3
Protein: p.Ala1112=
Coding: c.3336T>C
MANE Select: NM_153240
dbSNP: rs188431787
Type: single nucleotide variant
Location: chr3:132684788 (GRCh38)
Gene constraint: LOEUF 0.873 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.59 · 1 PDB

Full NPHP3 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

For Nephronophthisis (Orphanet):

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

Similar variants

NPHP3 c.1985+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP3 c.3201+1G>T Likely pathogenic ★★ same condition
NPHP3 c.393+1G>C Likely pathogenic ★★ same condition
NPHP3 c.958-2A>G Pathogenic ★★ same condition
NPHP3 p.Arg1125Ter Pathogenic ★★ same condition
NPHP3 p.Arg1259Ter Pathogenic/Likely pathogenic ★★ same condition
NPHP3 p.Arg142Ter Pathogenic/Likely pathogenic ★★ same condition
NPHP3 p.Arg577Ter 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/nphp3-p-ala1112 (accessed [today's date]).

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