Is NPHP1 p.Arg541Gly (c.1621A>G) pathogenic?

NPHP1 p.Arg541Gly (c.1621A>G) is classified Uncertain significance in NPHP1 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-10-18). AlphaMissense: likely benign (0.2422); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with NPHP1 p.Arg541Gly (c.1621A>G)?

NPHP1 p.Arg541Gly (c.1621A>G) is associated with Inborn genetic diseases (ClinVar).

How common is NPHP1 p.Arg541Gly (c.1621A>G) in the general population?

NPHP1 p.Arg541Gly (c.1621A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about NPHP1 p.Arg541Gly (c.1621A>G)?

AlphaMissense predicts likely benign (score 0.2422) — an in-silico prediction, not a clinical call.

NPHP1 p.Arg541Gly

c.1621A>G · VCV3355515

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2422 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2422	likely benign
REVEL	0.563	indeterminate
SaProt	LLR -14.38	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 1.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R596G vs ClinVar R541G) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,844 alleles

Overall 0.000124% 2/1,611,902 alleles · very rare exomes 2/1,459,554 · genomes 0/152,348 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,844
Remaining individualsnot grpmax-eligible	0.0016%	62,434

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.Arg541Gly
Coding: c.1621A>G
MANE Select: NM_001128178
Type: single nucleotide variant
Location: chr2:110131700 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NPHP1 p.Arg541= Likely benign ★ 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-arg541gly (accessed [today's date]).

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