Is NPHP1 p.Pro615Ser (c.1843C>T) pathogenic?

NPHP1 p.Pro615Ser (c.1843C>T) is classified Uncertain significance in NPHP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-20). AlphaMissense: likely benign (0.1841); Very rare (popmax 0.00267%, afr).

How common is NPHP1 p.Pro615Ser (c.1843C>T) in the general population?

NPHP1 p.Pro615Ser (c.1843C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about NPHP1 p.Pro615Ser (c.1843C>T)?

AlphaMissense predicts likely benign (score 0.1841) — an in-silico prediction, not a clinical call.

NPHP1 p.Pro615Ser

c.1843C>T · VCV4070880

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1841 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1841	likely benign
REVEL	0.356	indeterminate
SaProt	LLR -8.51	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.32 · evaluated, not missing
Pangolin	Δ0.22	gain · loss 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 6.3	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	26.6	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 P670S vs ClinVar P615S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,930 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,613,976 alleles · very rare exomes 0/1,461,772 · genomes 2/152,204 · 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.Pro615Ser
Coding: c.1843C>T
MANE Select: NM_001128178
Type: single nucleotide variant
Location: chr2:110123982 (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

Similar variants

NPHP1 p.Pro615= Likely benign ★ same residue
NPHP1 c.1083+1G>A Likely pathogenic ★★ same type
NPHP1 c.1270-1G>A Pathogenic ★★ same type
NPHP1 c.1270-2A>G Pathogenic/Likely pathogenic ★★ same type
NPHP1 c.143+1G>C Likely pathogenic ★★ same type
NPHP1 c.144-1G>A Pathogenic/Likely pathogenic ★★ same type
NPHP1 c.1716+1G>T Pathogenic/Likely pathogenic ★★ same type
NPHP1 c.329+1G>A Pathogenic/Likely pathogenic ★★ same type

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-pro615ser (accessed [today's date]).

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