Is NPHP3 p.Met1Thr (c.2T>C) pathogenic?

NPHP3 p.Met1Thr (c.2T>C) is classified Pathogenic/Likely pathogenic in NPHP3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-05). Very rare (popmax 0.00555%, afr); Associated with nephronophthisis 3.

What condition is associated with NPHP3 p.Met1Thr (c.2T>C)?

NPHP3 p.Met1Thr (c.2T>C) is associated with nephronophthisis 3, renal-hepatic-pancreatic dysplasia 1, NPHP3-related Meckel-like syndrome (ClinVar).

How common is NPHP3 p.Met1Thr (c.2T>C) in the general population?

NPHP3 p.Met1Thr (c.2T>C) is very rare (popmax 0.00555%, afr) (gnomAD).

How is Nephronophthisis inherited?

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

NPHP3 p.Met1Thr

c.2T>C · rs886041990 · VCV280859

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00555%, afr)

Conditions

nephronophthisis 3

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.725	pathogenic-leaning
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 8.3	GERP 1.3, phastCons 1
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00555% African / African-American · 4/72,088 alleles

Filtering AF 0.00189% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00107%

Overall 0.000317% 5/1,575,880 alleles · very rare exomes 3/1,424,498 · genomes 2/151,382 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00555%	18,022
Remaining individualsnot grpmax-eligible	0.00163%	61,322

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.Met1Thr
Coding: c.2T>C
MANE Select: NM_153240
dbSNP: rs886041990
Type: single nucleotide variant
Location: chr3:132722354 (GRCh38)

Full NPHP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nephronophthisis 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: renal-hepatic-pancreatic dysplasia 1 NPHP3-related Meckel-like syndrome

For Nephronophthisis (Orphanet):

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

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-met1thr (accessed [today's date]).

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