Is RNLS p.Leu80Pro (c.239T>C) pathogenic?

RNLS p.Leu80Pro (c.239T>C) is classified Uncertain significance in RNLS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-25). AlphaMissense: likely pathogenic (0.8696); Ultra-rare (popmax 0.0739%, eas).

How common is RNLS p.Leu80Pro (c.239T>C) in the general population?

RNLS p.Leu80Pro (c.239T>C) is ultra-rare (popmax 0.0739%, eas) (gnomAD).

What do computational predictors say about RNLS p.Leu80Pro (c.239T>C)?

AlphaMissense predicts likely pathogenic (score 0.8696) — an in-silico prediction, not a clinical call.

RNLS p.Leu80Pro

c.239T>C · rs747214534 · VCV2603694

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8696 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0739%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8696	likely pathogenic · top 8% in RNLS
REVEL	0.855	moderately pathogenic-leaning
SaProt	LLR -12.02	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 298 kb · p 0.87 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0739% East Asian · 32/43,312 alleles

Filtering AF 0.0537% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0468%

Overall 0.0021% 33/1,571,880 alleles · ultra-rare exomes 29/1,419,712 · genomes 4/152,168 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0739%	1,354
Remaining individualsnot grpmax-eligible	0.00165%	60,466

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: RNLS
Protein: p.Leu80Pro
Coding: c.239T>C
MANE Select: NM_001031709
dbSNP: rs747214534
Type: single nucleotide variant
Location: chr10:88581695 (GRCh38)
Gene constraint: LOEUF 1.206 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.79 · 1 PDB
Residue 80: an α-helix

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

Similar variants

RNLS p.Asp102Glu Uncertain significance ★★ ⚠ same type
RNLS p.His307Leu Uncertain significance ★★ ⚠ same type
RNLS p.Ile226Thr Uncertain significance ★★ ⚠ same type
RNLS p.Leu335Pro Uncertain significance ★★ ⚠ same type
RNLS p.Pro249Leu Uncertain significance ★★ ⚠ same type
RNLS p.Ser217Gly Uncertain significance ★★ ⚠ same type
RNLS p.Thr160Pro Uncertain significance ★★ ⚠ same type
RNLS c.224+115A>G Benign ★★ 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/rnls-p-leu80pro (accessed [today's date]).

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