Is NPHP4 p.Ala649Asp (c.1946C>A) pathogenic?

NPHP4 p.Ala649Asp (c.1946C>A) is classified Uncertain significance in NPHP4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-10). AlphaMissense: likely pathogenic (0.9526); Very rare (popmax 0.000679%, nfe); Associated with Inborn genetic diseases.

What condition is associated with NPHP4 p.Ala649Asp (c.1946C>A)?

NPHP4 p.Ala649Asp (c.1946C>A) is associated with Inborn genetic diseases (ClinVar).

How common is NPHP4 p.Ala649Asp (c.1946C>A) in the general population?

NPHP4 p.Ala649Asp (c.1946C>A) is very rare (popmax 0.000679%, nfe) (gnomAD).

What do computational predictors say about NPHP4 p.Ala649Asp (c.1946C>A)?

AlphaMissense predicts likely pathogenic (score 0.9526) — an in-silico prediction, not a clinical call.

NPHP4 p.Ala649Asp

c.1946C>A · VCV3921398

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9526 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000679%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9526	likely pathogenic · top 3% in NPHP4
REVEL	0.976	strongly pathogenic-leaning
SaProt	LLR -5.69	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	27.3	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 0.000679% European (non-Finnish) · 8/1,177,944 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.00062% 10/1,611,748 alleles · very rare exomes 9/1,459,544 · genomes 1/152,204 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00312%	32,010
European (non-Finnish)grpmax	0.000679%	147,243

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: NPHP4
Protein: p.Ala649Asp
Coding: c.1946C>A
MANE Select: NM_015102
Type: single nucleotide variant
Location: chr1:5905301 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NPHP4 p.Ala1220Val Uncertain significance ★★ ⚠ same condition
NPHP4 p.Ala1263Gly Uncertain significance ★★ ⚠ same condition
NPHP4 p.Ala678Thr Uncertain significance ★★ ⚠ same condition
NPHP4 p.Ala956Thr Uncertain significance ★★ ⚠ same condition
NPHP4 p.Ala988Thr Uncertain significance ★★ ⚠ same condition
NPHP4 p.Arg1109Gln Uncertain significance ★★ ⚠ same condition
NPHP4 p.Arg1135Cys Uncertain significance ★★ ⚠ same condition
NPHP4 p.Arg1149His Uncertain significance ★★ ⚠ 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-ala649asp (accessed [today's date]).

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