Is NPHP3 p.Ala1221Val (c.3662C>T) pathogenic?

NPHP3 p.Ala1221Val (c.3662C>T) is classified Conflicting classifications of pathogenicity in NPHP3 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-28). AlphaMissense: likely pathogenic (0.773); Rare (popmax 0.136%, sas); Associated with nephronophthisis.

What condition is associated with NPHP3 p.Ala1221Val (c.3662C>T)?

NPHP3 p.Ala1221Val (c.3662C>T) is associated with nephronophthisis, optic atrophy, renal-hepatic-pancreatic dysplasia 1 (ClinVar).

How common is NPHP3 p.Ala1221Val (c.3662C>T) in the general population?

NPHP3 p.Ala1221Val (c.3662C>T) is rare (popmax 0.136%, sas) (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.Ala1221Val (c.3662C>T)?

AlphaMissense predicts likely pathogenic (score 0.773) — an in-silico prediction, not a clinical call.

NPHP3 p.Ala1221Val

c.3662C>T · rs202048210 · VCV288174

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.773 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.136%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.773	likely pathogenic
REVEL	0.777	moderately pathogenic-leaning
SaProt	LLR -7.94	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 10	GERP 2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0019 · regional, not allelic
Overall
CADD	27.3	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 0.136% South Asian · 124/91,050 alleles

Filtering AF 0.117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.109%

Overall 0.0178% 287/1,613,136 alleles · rare exomes 268/1,460,920 · genomes 19/152,216 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.136%	734
Middle Eastern	0.033%	3,029
Remaining individualsnot grpmax-eligible	0.0192%	5,204
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,393
European (non-Finnish)	0.0116%	8,608
Admixed American	0.00666%	15,004
Finnishnot grpmax-eligible	0.00469%	21,331
East Asian	0.00223%	44,788

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.Ala1221Val
Coding: c.3662C>T
MANE Select: NM_153240
dbSNP: rs202048210
Type: single nucleotide variant
Location: chr3:132683433 (GRCh38)
Gene constraint: LOEUF 0.873 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.59 · 1 PDB
Residue 1221: a UniProt-annotated variant site (in nphp3)

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

Also linked: optic atrophy renal-hepatic-pancreatic dysplasia 1 NPHP3-related Meckel-like syndrome nephronophthisis 3

For Nephronophthisis (Orphanet):

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

Similar variants

NPHP3 p.Ala1221= Benign/Likely benign ★★ 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.520-1G>T Pathogenic ★★ same condition
NPHP3 c.823+1G>T Likely pathogenic ★★ same condition
NPHP3 c.958-2A>G Pathogenic ★★ same condition
NPHP3 p.Arg1125Ter 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-ala1221val (accessed [today's date]).

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