Is ARL8A p.Arg58Ser (c.172C>A) pathogenic?

ARL8A p.Arg58Ser (c.172C>A) is classified Uncertain significance in ARL8A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-14). AlphaMissense: likely pathogenic (0.9914); Very rare (popmax 8.47e-05%, nfe).

How common is ARL8A p.Arg58Ser (c.172C>A) in the general population?

ARL8A p.Arg58Ser (c.172C>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ARL8A p.Arg58Ser (c.172C>A)?

AlphaMissense predicts likely pathogenic (score 0.9914) — an in-silico prediction, not a clinical call.

ARL8A p.Arg58Ser

c.172C>A · VCV4146264

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9914 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9914	likely pathogenic
REVEL	0.562	indeterminate
SaProt	LLR -13.80	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP -3.5, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 10 kb · p 2.8e-13 · regional, not allelic
Overall
CADD	29.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.47e-05% European (non-Finnish) · 1/1,179,964 alleles

Overall 6.84e-05% 1/1,461,824 alleles · very rare

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: ARL8A
Protein: p.Arg58Ser
Coding: c.172C>A
MANE Select: NM_138795
Type: single nucleotide variant
Location: chr1:202138400 (GRCh38)
Gene constraint: LOEUF 0.58 · pLI 0.84 (gnomAD)
Structure: AlphaFold pLDDT 91.87 · 3 PDB
Residue 58: a β-strand

Full ARL8A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARL8A p.Ala137= Benign ★★ same type
ARL8A p.Gln153= Benign ★★ same type
ARL8A p.Ala3Thr Uncertain significance ★ ⚠ same type
ARL8A p.Asp100Gly Uncertain significance ★ ⚠ same type
ARL8A p.Glu156Gln Uncertain significance ★ ⚠ same type
ARL8A p.Ile2Met Uncertain significance ★ ⚠ same type
ARL8A p.Val93Met 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/arl8a-p-arg58ser (accessed [today's date]).

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