Is NPHP3 p.Ala1221= (c.3663C>T) pathogenic?

NPHP3 p.Ala1221= (c.3663C>T) is classified Benign/Likely benign in NPHP3 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-20). Rare (popmax 0.475%, afr); Associated with NPHP3-related Meckel-like syndrome.

What condition is associated with NPHP3 p.Ala1221= (c.3663C>T)?

NPHP3 p.Ala1221= (c.3663C>T) is associated with NPHP3-related Meckel-like syndrome, kidney disorder, renal-hepatic-pancreatic dysplasia 1 (ClinVar).

How common is NPHP3 p.Ala1221= (c.3663C>T) in the general population?

NPHP3 p.Ala1221= (c.3663C>T) is rare (popmax 0.475%, afr) (gnomAD).

NPHP3 p.Ala1221=

c.3663C>T · rs112144165 · VCV262707

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

rare (popmax 0.475%, afr)

Conditions

NPHP3-related Meckel-like syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -0.69, phastCons 1
Overall
CADD	8.23	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.475% African / African-American · 356/74,994 alleles

Filtering AF 0.434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.418%

Overall 0.0299% 483/1,613,168 alleles · rare exomes 302/1,460,938 · genomes 181/152,230 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.475%	211
Middle Eastern	0.116%	865
Remaining individualsnot grpmax-eligible	0.112%	892
Admixed American	0.065%	1,539
South Asian	0.00439%	22,765
European (non-Finnish)	0.000594%	168,476

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.Ala1221=
Coding: c.3663C>T
MANE Select: NM_153240
dbSNP: rs112144165
Type: single nucleotide variant
Location: chr3:132683432 (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

Also linked: kidney disorder renal-hepatic-pancreatic dysplasia 1 nephronophthisis 3 nephronophthisis

Similar variants

NPHP3 p.Ala1221Val Conflicting classifications of pathogenicity ★ ⚠ 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-ala1221 (accessed [today's date]).

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