Is NPHP3 p.Ser693Arg (c.2077A>C) pathogenic?

NPHP3 p.Ser693Arg (c.2077A>C) is classified Uncertain significance in NPHP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-31). AlphaMissense: ambiguous (0.4129); Very rare (popmax 0.00447%, eas); Associated with Inborn genetic diseases.

What condition is associated with NPHP3 p.Ser693Arg (c.2077A>C)?

NPHP3 p.Ser693Arg (c.2077A>C) is associated with Inborn genetic diseases (ClinVar).

How common is NPHP3 p.Ser693Arg (c.2077A>C) in the general population?

NPHP3 p.Ser693Arg (c.2077A>C) is very rare (popmax 0.00447%, eas) (gnomAD).

What do computational predictors say about NPHP3 p.Ser693Arg (c.2077A>C)?

AlphaMissense predicts ambiguous (score 0.4129) — an in-silico prediction, not a clinical call.

NPHP3 p.Ser693Arg

c.2077A>C · rs1449744400 · VCV2293253

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4129 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00447%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4129	ambiguous
REVEL	0.177	moderately benign-leaning
SaProt	LLR -9.42	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 0.84, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 30 kb · p 0.87 · regional, not allelic
Overall
CADD	20.8	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 0.00447% East Asian · 2/44,738 alleles

Filtering AF 0.000741% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000125% 2/1,602,422 alleles · very rare exomes 0/1,450,184 · genomes 2/152,238 · 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.Ser693Arg
Coding: c.2077A>C
MANE Select: NM_153240
dbSNP: rs1449744400
Type: single nucleotide variant
Location: chr3:132697271 (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.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
NPHP3 p.Gly235Arg 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-ser693arg (accessed [today's date]).

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