Is NPHP4 p.Val1236Met (c.3706G>A) pathogenic?

NPHP4 p.Val1236Met (c.3706G>A) is classified Uncertain significance in NPHP4 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-06-20). AlphaMissense: likely benign (0.184); Ultra-rare (popmax 0.0666%, mid); Associated with NPHP4-related disorder.

What condition is associated with NPHP4 p.Val1236Met (c.3706G>A)?

NPHP4 p.Val1236Met (c.3706G>A) is associated with NPHP4-related disorder, nephronophthisis 4, Senior-Loken syndrome 4 (ClinVar).

How common is NPHP4 p.Val1236Met (c.3706G>A) in the general population?

NPHP4 p.Val1236Met (c.3706G>A) is ultra-rare (popmax 0.0666%, mid) (gnomAD).

What do computational predictors say about NPHP4 p.Val1236Met (c.3706G>A)?

AlphaMissense predicts likely benign (score 0.184) — an in-silico prediction, not a clinical call.

NPHP4 p.Val1236Met

c.3706G>A · rs781049266 · VCV1056125

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.184 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0666%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

NPHP4-related disorder

Computational evidence

Protein change
AlphaMissense	0.184	likely benign
REVEL	0.441	indeterminate
SaProt	LLR -8.58	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 1.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	22.9	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 0.0666% Middle Eastern · 4/6,008 alleles

Filtering AF 0.0227% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0189%

Overall 0.00703% 113/1,607,404 alleles · ultra-rare exomes 102/1,455,092 · genomes 11/152,312 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0666%	1,502
South Asian	0.0309%	3,237
Remaining individualsnot grpmax-eligible	0.00965%	10,360
East Asian	0.00671%	14,895
European (non-Finnish)	0.00587%	17,044
African / African-American	0.004%	24,974

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.Val1236Met
Coding: c.3706G>A
MANE Select: NM_015102
dbSNP: rs781049266
Type: single nucleotide variant
Location: chr1:5865212 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 1236: the 'sufficient for basal bodies localization' region; a UniProt-annotated variant site (found in a patient with cardiac laterality defects; fails to rescue heart looping defects in zebrafish knockout)

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

Disease context

Also linked: nephronophthisis 4 Senior-Loken syndrome 4 nephronophthisis

Similar variants

NPHP4 c.2304+1G>A Pathogenic ★★ same condition
NPHP4 c.2611+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.2611+1G>C Pathogenic ★★ same condition
NPHP4 c.3644+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.3644+1G>T Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.517+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.518-2A>G Likely pathogenic ★★ same condition
NPHP4 c.992+2T>C 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/nphp4-p-val1236met (accessed [today's date]).

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