Is NPHP1 p.Ser29Phe (c.86C>T) pathogenic?

NPHP1 p.Ser29Phe (c.86C>T) is classified Uncertain significance in NPHP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-21). AlphaMissense: likely benign (0.2411); Very rare (popmax 0.00153%, nfe).

How common is NPHP1 p.Ser29Phe (c.86C>T) in the general population?

NPHP1 p.Ser29Phe (c.86C>T) is very rare (popmax 0.00153%, nfe) (gnomAD).

What do computational predictors say about NPHP1 p.Ser29Phe (c.86C>T)?

AlphaMissense predicts likely benign (score 0.2411) — an in-silico prediction, not a clinical call.

NPHP1 p.Ser29Phe

c.86C>T · VCV3391542

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2411 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2411	likely benign
REVEL	0.03	moderately benign-leaning
SaProt	LLR -9.32	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 0.84, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	20.8	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 0.00153% European (non-Finnish) · 18/1,177,046 alleles

Filtering AF 0.000956% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000789%

Overall 0.00304% 49/1,609,518 alleles · very rare exomes 44/1,457,326 · genomes 5/152,192 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0412%	2,427
Remaining individualsnot grpmax-eligible	0.00802%	12,473
European (non-Finnish)grpmax	0.00153%	65,392

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser29Phe
Coding: c.86C>T
MANE Select: NM_001128178
Type: single nucleotide variant
Location: chr2:110201478 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.22 · 2 PDB
Residue 29: an α-helix

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

Similar variants

NPHP1 p.Ser29fs Pathogenic ★★ 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-ser29phe (accessed [today's date]).

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