Is NPHP3 p.Arg1074His (c.3221G>A) pathogenic?

NPHP3 p.Arg1074His (c.3221G>A) is classified Likely benign in NPHP3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-25). AlphaMissense: likely benign (0.1279); Rare (popmax 0.428%, afr); Associated with nephronophthisis.

What condition is associated with NPHP3 p.Arg1074His (c.3221G>A)?

NPHP3 p.Arg1074His (c.3221G>A) is associated with nephronophthisis (ClinVar).

How common is NPHP3 p.Arg1074His (c.3221G>A) in the general population?

NPHP3 p.Arg1074His (c.3221G>A) is rare (popmax 0.428%, afr) (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.Arg1074His (c.3221G>A)?

AlphaMissense predicts likely benign (score 0.1279) — an in-silico prediction, not a clinical call.

NPHP3 p.Arg1074His

c.3221G>A · rs144781228 · VCV281975

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1279 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.428%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.1279	likely benign
REVEL	0.473	indeterminate
SaProt	LLR -5.83	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0019 · regional, not allelic
Overall
CADD	26.6	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 0.428% African / African-American · 321/75,012 alleles

Filtering AF 0.389% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.374%

Overall 0.0312% 504/1,613,932 alleles · rare exomes 282/1,461,742 · genomes 222/152,190 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.428%	234
Admixed American	0.0983%	1,017
Remaining individualsnot grpmax-eligible	0.0336%	2,976
Middle Eastern	0.0165%	6,062
South Asian	0.0132%	7,588
East Asian	0.00892%	11,212
European (non-Finnish)	0.0072%	13,882
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600

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.Arg1074His
Coding: c.3221G>A
MANE Select: NM_153240
dbSNP: rs144781228
Type: single nucleotide variant
Location: chr3:132686368 (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

For Nephronophthisis (Orphanet):

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

Similar variants

NPHP3 p.Arg1074Cys 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.958-2A>G Pathogenic ★★ same condition
NPHP3 p.Arg1125Ter Pathogenic ★★ same condition
NPHP3 p.Arg1259Ter Pathogenic/Likely pathogenic ★★ same condition
NPHP3 p.Arg142Ter Pathogenic/Likely 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-arg1074his (accessed [today's date]).

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