Is NPHP3 p.Thr136Pro (c.406A>C) pathogenic?

NPHP3 p.Thr136Pro (c.406A>C) is classified Uncertain significance in NPHP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2016-09-26). AlphaMissense: likely pathogenic (0.9361); Very rare (popmax 0.00134%, afr).

How common is NPHP3 p.Thr136Pro (c.406A>C) in the general population?

NPHP3 p.Thr136Pro (c.406A>C) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about NPHP3 p.Thr136Pro (c.406A>C)?

AlphaMissense predicts likely pathogenic (score 0.9361) — an in-silico prediction, not a clinical call.

NPHP3 p.Thr136Pro

c.406A>C · rs1553775408 · VCV497600

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9361 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9361	likely pathogenic · top 8% in NPHP3
REVEL	0.676	pathogenic-leaning
SaProt	LLR -9.92	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 7.9	GERP 0.26, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 30 kb · p 0.87 · regional, not allelic
Overall
CADD	26.9	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 0.00134% African / African-American · 1/74,660 alleles

Overall 6.29e-05% 1/1,589,114 alleles · very rare exomes 1/1,437,196 · genomes 0/151,918 · joint denominator

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.Thr136Pro
Coding: c.406A>C
MANE Select: NM_153240
dbSNP: rs1553775408
Type: single nucleotide variant
Location: chr3:132719818 (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

Similar variants

NPHP3 p.Thr136= Conflicting classifications of pathogenicity ★ same residue
NPHP3 p.Thr136fs Pathogenic/Likely pathogenic ★★ same residue
NPHP3 c.1985+1G>A Pathogenic/Likely pathogenic ★★ same type
NPHP3 c.3201+1G>T Likely pathogenic ★★ same type
NPHP3 c.393+1G>C Likely pathogenic ★★ same type
NPHP3 c.520-1G>T Pathogenic ★★ same type
NPHP3 c.823+1G>T Likely pathogenic ★★ same type
NPHP3 c.958-2A>G Pathogenic ★★ same type

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-thr136pro (accessed [today's date]).

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