Is NPHP3 p.Ala1184Thr (c.3550G>A) pathogenic?

NPHP3 p.Ala1184Thr (c.3550G>A) is classified Conflicting classifications of pathogenicity in NPHP3 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-04-01). AlphaMissense: likely pathogenic (0.9232); Low-frequency (popmax 1.03%, sas); Associated with nephronophthisis.

What condition is associated with NPHP3 p.Ala1184Thr (c.3550G>A)?

NPHP3 p.Ala1184Thr (c.3550G>A) is associated with nephronophthisis, renal-hepatic-pancreatic dysplasia 1, NPHP3-related Meckel-like syndrome (ClinVar).

How common is NPHP3 p.Ala1184Thr (c.3550G>A) in the general population?

NPHP3 p.Ala1184Thr (c.3550G>A) is low-frequency (popmax 1.03%, sas) (gnomAD).

How is Nephronophthisis inherited?

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

What do computational predictors say about NPHP3 p.Ala1184Thr (c.3550G>A)?

AlphaMissense predicts likely pathogenic (score 0.9232) — an in-silico prediction, not a clinical call.

NPHP3 p.Ala1184Thr

c.3550G>A · rs34391943 · VCV167378

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.9232 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.03%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.9232	likely pathogenic · top 9% in NPHP3
REVEL	0.788	moderately pathogenic-leaning
SaProt	LLR -8.06	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 0.75, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0019 · regional, not allelic
Overall
CADD	25.2	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 1.03% South Asian · 942/91,078 alleles

Filtering AF 0.979% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.957%

Overall 0.877% 14,148/1,613,890 alleles · low-frequency exomes 13,008/1,461,630 · genomes 1,140/152,260 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	2.14%	47
Finnishnot grpmax-eligible	1.33%	75
South Asiangrpmax	1.03%	97
European (non-Finnish)	0.924%	108
Remaining individualsnot grpmax-eligible	0.923%	108
Middle Eastern	0.429%	233
Admixed American	0.198%	504
African / African-American	0.128%	782
East Asian	0.00891%	11,218

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala1184Thr
Coding: c.3550G>A
MANE Select: NM_153240
dbSNP: rs34391943
Type: single nucleotide variant
Location: chr3:132684574 (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

Also linked: renal-hepatic-pancreatic dysplasia 1 NPHP3-related Meckel-like syndrome nephronophthisis 3 Bardet-Biedl syndrome

For Nephronophthisis (Orphanet):

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

Similar variants

NPHP3 p.Ala1184Val Uncertain significance ★ ⚠ same residue
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.520-1G>T Pathogenic ★★ same condition
NPHP3 c.823+1G>T Likely pathogenic ★★ same condition
NPHP3 c.958-2A>G Pathogenic ★★ same condition
NPHP3 p.Arg1125Ter 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-ala1184thr (accessed [today's date]).

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