Is RNLS p.Ala70Val (c.209C>T) pathogenic?

RNLS p.Ala70Val (c.209C>T) is classified Uncertain significance in RNLS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-21). AlphaMissense: likely benign (0.1258); Very rare (popmax 0.0028%, nfe).

How common is RNLS p.Ala70Val (c.209C>T) in the general population?

RNLS p.Ala70Val (c.209C>T) is very rare (popmax 0.0028%, nfe) (gnomAD).

What do computational predictors say about RNLS p.Ala70Val (c.209C>T)?

AlphaMissense predicts likely benign (score 0.1258) — an in-silico prediction, not a clinical call.

RNLS p.Ala70Val

c.209C>T · rs767642829 · VCV2338047

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1258 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0028%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1258	likely benign
REVEL	0.301	indeterminate
SaProt	LLR -6.49	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 0.85, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 298 kb · p 0.87 · regional, not allelic
Overall
CADD	23.4	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 0.0028% European (non-Finnish) · 33/1,179,256 alleles

Filtering AF 0.002% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00176%

Overall 0.00211% 34/1,612,438 alleles · very rare exomes 34/1,460,186 · genomes 0/152,252 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0028%	35,735
Remaining individualsnot grpmax-eligible	0.0016%	62,434

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.Ala70Val
Coding: c.209C>T
MANE Select: NM_001031709
dbSNP: rs767642829
Type: single nucleotide variant
Location: chr10:88582217 (GRCh38)
Gene constraint: LOEUF 1.206 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.79 · 1 PDB
Residue 70: an α-helix

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

Similar variants

RNLS p.Ala70Ser Uncertain significance ★ ⚠ same residue
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

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-ala70val (accessed [today's date]).

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