Is NPHP1 p.Gly644Arg (c.1930G>C) pathogenic?

NPHP1 p.Gly644Arg (c.1930G>C) is classified Likely pathogenic in NPHP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2016-06-01). AlphaMissense: ambiguous (0.4005); Ultra-rare (popmax 0.0111%, eas).

How common is NPHP1 p.Gly644Arg (c.1930G>C) in the general population?

NPHP1 p.Gly644Arg (c.1930G>C) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about NPHP1 p.Gly644Arg (c.1930G>C)?

AlphaMissense predicts ambiguous (score 0.4005) — an in-silico prediction, not a clinical call.

NPHP1 p.Gly644Arg

c.1930G>C · rs760619900 · VCV425213

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4005 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Computational evidence

Protein change
AlphaMissense	0.4005	ambiguous
REVEL	0.378	indeterminate
SaProt	LLR -3.36	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.6	GERP 0.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM G699R vs ClinVar G644R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0111% East Asian · 5/44,880 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00031% 5/1,614,052 alleles · ultra-rare exomes 5/1,461,862 · genomes 0/152,190 · 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: NPHP1
Protein: p.Gly644Arg
Coding: c.1930G>C
MANE Select: NM_001128178
dbSNP: rs760619900
Type: single nucleotide variant
Location: chr2:110123895 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.22 · 2 PDB

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

Similar variants

NPHP1 p.Gly644= Conflicting classifications of pathogenicity ★ 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-gly644arg (accessed [today's date]).

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