Is NPHP1 p.Val264Met (c.790G>A) pathogenic?

NPHP1 p.Val264Met (c.790G>A) is classified Uncertain significance in NPHP1 (ClinVar, Single submitter, 2 submitters; last evaluated 2018-05-03). AlphaMissense: likely benign (0.1326); Ultra-rare (popmax 0.0165%, mid); Associated with inherited retinal dystrophy.

What condition is associated with NPHP1 p.Val264Met (c.790G>A)?

NPHP1 p.Val264Met (c.790G>A) is associated with inherited retinal dystrophy (ClinVar).

How common is NPHP1 p.Val264Met (c.790G>A) in the general population?

NPHP1 p.Val264Met (c.790G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about NPHP1 p.Val264Met (c.790G>A)?

AlphaMissense predicts likely benign (score 0.1326) — an in-silico prediction, not a clinical call.

NPHP1 p.Val264Met

c.790G>A · rs1559074346 · VCV597068

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1326 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.1326	likely benign
REVEL	0.189	benign-leaning
SaProt	LLR -7.62	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.20	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP -0.22	GERP -0.16
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	13.55	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V319M vs ClinVar V264M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,058 alleles

Overall 6.2e-05% 1/1,612,462 alleles · ultra-rare exomes 1/1,460,198 · genomes 0/152,264 · 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: NPHP1
Protein: p.Val264Met
Coding: c.790G>A
MANE Select: NM_001128178
dbSNP: rs1559074346
Type: single nucleotide variant
Location: chr2:110163117 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.22 · 2 PDB

Full NPHP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NPHP1 p.Val264= Likely benign ★ same residue
NPHP1 p.Gly287Arg Pathogenic ★★ same condition
NPHP1 p.Glu226Asp Uncertain significance ★★ ⚠ same condition
NPHP1 c.771+2C>T Conflicting classifications of pathogenicity ★ ⚠ same condition
NPHP1 p.Leu511= Conflicting classifications of pathogenicity ★ same condition
NPHP1 p.Met268Thr Conflicting classifications of pathogenicity ★ ⚠ same condition
NPHP1 p.Thr267= Conflicting classifications of pathogenicity ★ same condition
NPHP1 p.Ile326Met 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-val264met (accessed [today's date]).

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