Is RNLS p.Ile93Val (c.277A>G) pathogenic?

RNLS p.Ile93Val (c.277A>G) is classified Conflicting classifications of pathogenicity in RNLS (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-01). AlphaMissense: likely benign (0.0748); Rare (popmax 0.506%, afr).

How common is RNLS p.Ile93Val (c.277A>G) in the general population?

RNLS p.Ile93Val (c.277A>G) is rare (popmax 0.506%, afr) (gnomAD).

What do computational predictors say about RNLS p.Ile93Val (c.277A>G)?

AlphaMissense predicts likely benign (score 0.0748) — an in-silico prediction, not a clinical call.

RNLS p.Ile93Val

c.277A>G · VCV3631572

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0748 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.506%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0748	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	LLR -5.04	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 2.9	GERP 0.47, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 298 kb · p 0.87 · regional, not allelic
Overall
CADD	14.4	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 0.506% African / African-American · 377/74,572 alleles

Filtering AF 0.463% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.447%

Overall 0.0359% 575/1,603,424 alleles · rare exomes 353/1,451,198 · genomes 222/152,226 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.506%	198
Admixed American	0.0717%	1,396
Remaining individualsnot grpmax-eligible	0.0532%	1,878
European (non-Finnish)	0.00987%	10,129
East Asian	0.00908%	11,009
South Asian	0.00336%	29,739

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.Ile93Val
Coding: c.277A>G
MANE Select: NM_001031709
Type: single nucleotide variant
Location: chr10:88581657 (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-ile93val (accessed [today's date]).

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