Is RNLS p.Val85Ile (c.253G>A) pathogenic?

RNLS p.Val85Ile (c.253G>A) is classified Conflicting classifications of pathogenicity in RNLS (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-04-01). AlphaMissense: likely benign (0.0606); Very rare (popmax 0.00408%, afr).

How common is RNLS p.Val85Ile (c.253G>A) in the general population?

RNLS p.Val85Ile (c.253G>A) is very rare (popmax 0.00408%, afr) (gnomAD).

What do computational predictors say about RNLS p.Val85Ile (c.253G>A)?

AlphaMissense predicts likely benign (score 0.0606) — an in-silico prediction, not a clinical call.

RNLS p.Val85Ile

c.253G>A · rs143513862 · VCV2177465

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0606 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00408%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0606	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -6.20	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.8	GERP -3.3
Regional constraint	o/e 0.99	unconstrained · MANE · 298 kb · p 0.87 · regional, not allelic
Overall
CADD	0.018	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 0.00408% African / African-American · 3/73,556 alleles

Filtering AF 0.00294% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00262%

Overall 0.0034% 54/1,588,352 alleles · very rare exomes 49/1,436,354 · genomes 5/151,998 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00408%	24,519
European (non-Finnish)	0.00385%	25,967
Admixed American	0.00355%	28,171
South Asian	0.00232%	43,026
East Asian	0.0023%	43,440
Remaining individualsnot grpmax-eligible	0.00163%	61,250

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.Val85Ile
Coding: c.253G>A
MANE Select: NM_001031709
dbSNP: rs143513862
Type: single nucleotide variant
Location: chr10:88581681 (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-val85ile (accessed [today's date]).

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