Is RNLS p.Pro49Arg (c.146C>G) pathogenic?

RNLS p.Pro49Arg (c.146C>G) is classified Uncertain significance in RNLS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). AlphaMissense: likely benign (0.108); Very rare (popmax 0.00667%, afr).

How common is RNLS p.Pro49Arg (c.146C>G) in the general population?

RNLS p.Pro49Arg (c.146C>G) is very rare (popmax 0.00667%, afr) (gnomAD).

What do computational predictors say about RNLS p.Pro49Arg (c.146C>G)?

AlphaMissense predicts likely benign (score 0.108) — an in-silico prediction, not a clinical call.

RNLS p.Pro49Arg

c.146C>G · VCV3947000

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.108 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.108	likely benign
REVEL	0.199	benign-leaning
SaProt	LLR -11.38	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 298 kb · p 0.87 · regional, not allelic
Overall
CADD	27.2	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 0.00667% African / African-American · 5/74,918 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.000434% 7/1,613,782 alleles · very rare exomes 4/1,461,556 · genomes 3/152,226 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,984
Remaining individualsnot grpmax-eligible	0.0032%	31,237

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.Pro49Arg
Coding: c.146C>G
MANE Select: NM_001031709
Type: single nucleotide variant
Location: chr10:88582280 (GRCh38)
Gene constraint: LOEUF 1.206 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.79 · 1 PDB

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-pro49arg (accessed [today's date]).

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