Is NRL p.Pro67Ser (c.199C>T) pathogenic?

NRL p.Pro67Ser (c.199C>T) is classified Conflicting classifications of pathogenicity in NRL (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-10-16). AlphaMissense: likely benign (0.0892); Ultra-rare (popmax 0.0164%, mid).

How common is NRL p.Pro67Ser (c.199C>T) in the general population?

NRL p.Pro67Ser (c.199C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about NRL p.Pro67Ser (c.199C>T)?

AlphaMissense predicts likely benign (score 0.0892) — an in-silico prediction, not a clinical call.

NRL p.Pro67Ser

c.199C>T · rs199691910 · VCV380387

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0892 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0892	likely benign
REVEL	0.184	benign-leaning
SaProt	LLR -9.01	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 0.93	GERP -0.13, phastCons 0.98
Regional constraint	o/e 0.96	unconstrained · MANE · 1,609 bp · p 0.51 · regional, not allelic
Overall
CADD	14.81	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00533%

Overall 0.00632% 102/1,613,942 alleles · ultra-rare exomes 92/1,461,696 · genomes 10/152,246 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Finnishnot grpmax-eligible	0.0125%	7,985
Admixed American	0.00833%	12,002
Remaining individualsnot grpmax-eligible	0.008%	12,497
European (non-Finnish)	0.00703%	14,217

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.Pro67Ser
Coding: c.199C>T
MANE Select: NM_001354768
dbSNP: rs199691910
Type: single nucleotide variant
Location: chr14:24082650 (GRCh38)
Gene constraint: LOEUF 1.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.42
Residue 67: a UniProt-annotated variant site (in rp27; no effect on phosphorylation; no effect on subcellular localization; no effect on transcriptional coactivator activity); the 'minimal transactivation domain (mtd)' region

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

Similar variants

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
NRL p.Ser50Pro Pathogenic/Likely pathogenic ★★ same type
NRL p.Tyr113Ter Pathogenic/Likely pathogenic ★★ same type
NRL c.381+3G>C Uncertain significance ★★ 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-pro67ser (accessed [today's date]).

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