Is NPHP3 p.Met635Leu (c.1903A>C) pathogenic?

NPHP3 p.Met635Leu (c.1903A>C) is classified Uncertain significance in NPHP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-05). AlphaMissense: likely benign (0.2158); Very rare (popmax 0.00892%, eas); Associated with Inborn genetic diseases.

What condition is associated with NPHP3 p.Met635Leu (c.1903A>C)?

NPHP3 p.Met635Leu (c.1903A>C) is associated with Inborn genetic diseases (ClinVar).

How common is NPHP3 p.Met635Leu (c.1903A>C) in the general population?

NPHP3 p.Met635Leu (c.1903A>C) is very rare (popmax 0.00892%, eas) (gnomAD).

What do computational predictors say about NPHP3 p.Met635Leu (c.1903A>C)?

AlphaMissense predicts likely benign (score 0.2158) — an in-silico prediction, not a clinical call.

NPHP3 p.Met635Leu

c.1903A>C · rs145166784 · VCV2517812

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2158 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00892%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2158	likely benign
REVEL	0.269	benign-leaning
SaProt	LLR -3.34	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.21	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 7.9	GERP 1.5, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 30 kb · p 0.87 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00892% East Asian · 4/44,854 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000248% 4/1,610,316 alleles · very rare exomes 2/1,457,960 · genomes 2/152,356 · 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.Met635Leu
Coding: c.1903A>C
MANE Select: NM_153240
dbSNP: rs145166784
Type: single nucleotide variant
Location: chr3:132699435 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NPHP3 p.Met635Val Uncertain significance ★ ⚠ same residue
NPHP3 p.Ala1203Val Uncertain significance ★★ ⚠ same condition
NPHP3 p.Arg605Cys Uncertain significance ★★ ⚠ same condition
NPHP3 p.Arg705His Uncertain significance ★★ ⚠ same condition
NPHP3 p.Arg756Trp Uncertain significance ★★ ⚠ same condition
NPHP3 p.Asn1097Ser Uncertain significance ★★ ⚠ same condition
NPHP3 p.Asn218Ser Uncertain significance ★★ ⚠ same condition
NPHP3 p.Asn776Ser Uncertain significance ★★ ⚠ 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-met635leu (accessed [today's date]).

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