Is NPHP1 p.Asp227Val (c.680A>T) pathogenic?

NPHP1 p.Asp227Val (c.680A>T) is classified Uncertain significance in NPHP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-19). AlphaMissense: likely benign (0.1172); Very rare (popmax 0.0011%, sas); Associated with Inborn genetic diseases.

What condition is associated with NPHP1 p.Asp227Val (c.680A>T)?

NPHP1 p.Asp227Val (c.680A>T) is associated with Inborn genetic diseases (ClinVar).

How common is NPHP1 p.Asp227Val (c.680A>T) in the general population?

NPHP1 p.Asp227Val (c.680A>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about NPHP1 p.Asp227Val (c.680A>T)?

AlphaMissense predicts likely benign (score 0.1172) — an in-silico prediction, not a clinical call.

NPHP1 p.Asp227Val

c.680A>T · rs2467374181 · VCV3201643

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1172 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1172	likely benign
REVEL	0.21	benign-leaning
SaProt	LLR -7.84	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.1	GERP -1.4, phastCons 0.79
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	18.06	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 0.0011% South Asian · 1/91,072 alleles

Overall 0.000124% 2/1,613,914 alleles · very rare exomes 2/1,461,608 · genomes 0/152,306 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,072
European (non-Finnish)	8.48e-05%	1,179,848

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: NPHP1
Protein: p.Asp227Val
Coding: c.680A>T
MANE Select: NM_001128178
dbSNP: rs2467374181
Type: single nucleotide variant
Location: chr2:110165100 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.22 · 2 PDB
Residue 227: the 'disordered' region

Full NPHP1 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

NPHP1 p.Asp227Glu Uncertain significance ★ ⚠ same residue
NPHP1 p.Gly287Arg Pathogenic ★★ same condition
NPHP1 c.771+136C>A Uncertain significance ★★ ⚠ same condition
NPHP1 c.771+26A>G Uncertain significance ★★ ⚠ same condition
NPHP1 c.771+38G>T Uncertain significance ★★ ⚠ same condition
NPHP1 p.Arg389His Uncertain significance ★★ ⚠ same condition
NPHP1 p.Arg628Gln Uncertain significance ★★ ⚠ same condition
NPHP1 p.Asn59His 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/nphp1-p-asp227val (accessed [today's date]).

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