Is NPHP1 p.Arg5Leu (c.14G>T) pathogenic?

NPHP1 p.Arg5Leu (c.14G>T) is classified Benign/Likely benign in NPHP1 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.2856); Low-frequency (popmax 4.49%, amr); Associated with intellectual disability, X-linked 102.

What condition is associated with NPHP1 p.Arg5Leu (c.14G>T)?

NPHP1 p.Arg5Leu (c.14G>T) is associated with intellectual disability, X-linked 102, Joubert syndrome 1, nephronophthisis 1 (ClinVar).

How common is NPHP1 p.Arg5Leu (c.14G>T) in the general population?

NPHP1 p.Arg5Leu (c.14G>T) is low-frequency (popmax 4.49%, amr) (gnomAD).

What do computational predictors say about NPHP1 p.Arg5Leu (c.14G>T)?

AlphaMissense predicts likely benign (score 0.2856) — an in-silico prediction, not a clinical call.

NPHP1 p.Arg5Leu

c.14G>T · rs190983114 · VCV129814

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.2856 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.49%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, X-linked 102

Computational evidence

Protein change
AlphaMissense	0.2856	likely benign
REVEL	0.203	benign-leaning
SaProt	LLR -7.58	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 0.9	GERP -0.2, phastCons 0.001
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	20.4	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.49% Admixed American · 2,694/60,026 alleles

Filtering AF 4.35% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.29%

Overall 0.182% 2,933/1,614,002 alleles · low-frequency exomes 2,369/1,461,680 · genomes 564/152,322 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	4.49%	22
Remaining individualsnot grpmax-eligible	0.176%	568
African / African-American	0.0959%	1,042
Middle Eastern	0.0165%	6,050
South Asian	0.011%	9,107
European (non-Finnish)	0.0039%	25,651

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.Arg5Leu
Coding: c.14G>T
MANE Select: NM_001128178
dbSNP: rs190983114
Type: single nucleotide variant
Location: chr2:110204955 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.22 · 2 PDB
Residue 5: a UniProt-annotated variant site (changed function; unable to rescue the corresponding loss of function zebrafish mutant which displays a cilium function alteration phenotype)

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

Disease context

intellectual disability, X-linked 102 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Joubert syndrome 1 nephronophthisis 1 Senior-Loken syndrome 1 Joubert syndrome with renal defect nephronophthisis

Similar variants

NPHP1 p.Arg5Pro Uncertain significance ★ ⚠ same residue
NPHP1 c.1083+1G>A Likely pathogenic ★★ same condition
NPHP1 c.1270-1G>A Pathogenic ★★ same condition
NPHP1 c.1270-2A>G Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.143+1G>C Likely pathogenic ★★ same condition
NPHP1 c.144-1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.1716+1G>T Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.329+1G>A Pathogenic/Likely pathogenic ★★ 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-arg5leu (accessed [today's date]).

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