Is NRL p.Pro4Ser (c.10C>T) pathogenic?

NRL p.Pro4Ser (c.10C>T) is classified Uncertain significance in NRL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-15). AlphaMissense: likely benign (0.1021); Very rare (popmax 6.2e-05%).

How common is NRL p.Pro4Ser (c.10C>T) in the general population?

NRL p.Pro4Ser (c.10C>T) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about NRL p.Pro4Ser (c.10C>T)?

AlphaMissense predicts likely benign (score 0.1021) — an in-silico prediction, not a clinical call.

NRL p.Pro4Ser

c.10C>T · rs1317207731 · VCV1911238

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1021 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1021	likely benign
REVEL	0.535	indeterminate
SaProt	LLR -6.35	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 3.1	GERP -0.12, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 1,609 bp · p 0.51 · regional, not allelic
Overall
CADD	21.1	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 6.2e-05%

Overall 6.2e-05% 1/1,612,086 alleles · very rare exomes 0/1,459,870 · genomes 1/152,216 · 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: NRL
Protein: p.Pro4Ser
Coding: c.10C>T
MANE Select: NM_001354768
dbSNP: rs1317207731
Type: single nucleotide variant
Location: chr14:24082839 (GRCh38)
Gene constraint: LOEUF 1.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.42

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

Similar variants

PCK2 p.Leu4Phe Uncertain significance ★★ ⚠ same residue
NRL p.Pro4Leu Uncertain significance ★ ⚠ same residue
PCK2 p.Leu4= Likely benign ★ same residue
NRL p.Arg31Ter Pathogenic/Likely pathogenic ★★ same type
NRL p.Pro51Leu Pathogenic/Likely pathogenic ★★ same type
NRL p.Pro51Ser Pathogenic/Likely pathogenic ★★ same type
NRL p.Pro51Thr Pathogenic/Likely pathogenic ★★ same type
NRL p.Ser50Leu 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/nrl-p-pro4ser (accessed [today's date]).

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