Is NPHP4 p.His1171Arg (c.3512A>G) pathogenic?

NPHP4 p.His1171Arg (c.3512A>G) is classified Uncertain significance in NPHP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-24). AlphaMissense: likely benign (0.1354); Very rare (popmax 0.000339%, nfe).

How common is NPHP4 p.His1171Arg (c.3512A>G) in the general population?

NPHP4 p.His1171Arg (c.3512A>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about NPHP4 p.His1171Arg (c.3512A>G)?

AlphaMissense predicts likely benign (score 0.1354) — an in-silico prediction, not a clinical call.

NPHP4 p.His1171Arg

c.3512A>G · VCV4912427

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1354 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1354	likely benign
REVEL	0.334	indeterminate
SaProt	LLR -9.27	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.9	GERP 2.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	19.51	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 0.000339% European (non-Finnish) · 4/1,179,610 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,166 alleles · very rare exomes 4/1,460,952 · genomes 0/152,214 · 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: NPHP4
Protein: p.His1171Arg
Coding: c.3512A>G
MANE Select: NM_015102
Type: single nucleotide variant
Location: chr1:5867076 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 1171: the 'sufficient for basal bodies localization' region

Full NPHP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NPHP4 p.His1171Leu Uncertain significance ★ ⚠ same residue
NPHP4 p.His1171Pro Uncertain significance ★ same residue
NPHP4 p.His1171= Likely benign ★ same residue
NPHP4 c.2304+1G>A Pathogenic ★★ same type
NPHP4 c.2611+1G>A Pathogenic/Likely pathogenic ★★ same type
NPHP4 c.2611+1G>C Pathogenic ★★ same type
NPHP4 c.3644+1G>A Pathogenic/Likely pathogenic ★★ same type
NPHP4 c.3644+1G>T 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/nphp4-p-his1171arg (accessed [today's date]).

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