Is RNLS p.Arg75Cys (c.223C>T) pathogenic?

RNLS p.Arg75Cys (c.223C>T) is classified Uncertain significance in RNLS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-22). AlphaMissense: likely benign (0.0787); Ultra-rare (popmax 0.0268%, amr).

How common is RNLS p.Arg75Cys (c.223C>T) in the general population?

RNLS p.Arg75Cys (c.223C>T) is ultra-rare (popmax 0.0268%, amr) (gnomAD).

What do computational predictors say about RNLS p.Arg75Cys (c.223C>T)?

AlphaMissense predicts likely benign (score 0.0787) — an in-silico prediction, not a clinical call.

RNLS p.Arg75Cys

c.223C>T · rs147588689 · VCV2320374

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0787 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0268%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0787	likely benign
REVEL	0.317	indeterminate
SaProt	LLR -6.77	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.23 · evaluated, not missing
Pangolin	Δ0.23	loss · gain 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 1.9	GERP 0.41, phastCons 0.97
Regional constraint	o/e 0.99	unconstrained · MANE · 298 kb · p 0.87 · regional, not allelic
Overall
CADD	24.2	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 0.0268% Admixed American · 16/59,762 alleles

Filtering AF 0.0168% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.00683% 110/1,610,924 alleles · ultra-rare exomes 76/1,458,644 · genomes 34/152,280 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0268%	3,735
African / African-American	0.024%	4,163
Remaining individualsnot grpmax-eligible	0.0176%	5,670
European (non-Finnish)	0.00535%	18,693
South Asian	0.0022%	45,434

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.Arg75Cys
Coding: c.223C>T
MANE Select: NM_001031709
dbSNP: rs147588689
Type: single nucleotide variant
Location: chr10:88582203 (GRCh38)
Gene constraint: LOEUF 1.206 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.79 · 1 PDB
Residue 75: 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-arg75cys (accessed [today's date]).

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