Is ARSI p.Arg543Ser (c.1627C>A) pathogenic?

ARSI p.Arg543Ser (c.1627C>A) is classified Uncertain significance in ARSI (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-24). AlphaMissense: likely benign (0.1442); Very rare (popmax 0.00187%, nfe).

How common is ARSI p.Arg543Ser (c.1627C>A) in the general population?

ARSI p.Arg543Ser (c.1627C>A) is very rare (popmax 0.00187%, nfe) (gnomAD).

What do computational predictors say about ARSI p.Arg543Ser (c.1627C>A)?

AlphaMissense predicts likely benign (score 0.1442) — an in-silico prediction, not a clinical call.

ARSI p.Arg543Ser

c.1627C>A · VCV3949451

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1442 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00187%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1442	likely benign
REVEL	0.302	indeterminate
SaProt	LLR -7.22	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 5,156 bp · p 0.021 · regional, not allelic
Overall
CADD	20.6	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 0.00187% European (non-Finnish) · 22/1,178,968 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00137% 22/1,610,938 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: ARSI
Protein: p.Arg543Ser
Coding: c.1627C>A
MANE Select: NM_001012301
Type: single nucleotide variant
Location: chr5:150297297 (GRCh38)
Gene constraint: LOEUF 1.403 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.35

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

Similar variants

ARSI p.Arg543His Uncertain significance ★★ ⚠ same residue
ARSI p.Arg543Cys Uncertain significance ★ ⚠ same residue
ARSI p.Ala216Thr Uncertain significance ★★ ⚠ same type
ARSI p.Ala259Val Uncertain significance ★★ ⚠ same type
ARSI p.Ala264Thr Uncertain significance ★★ ⚠ same type
ARSI p.Ala399Asp Uncertain significance ★★ ⚠ same type
ARSI p.Ala414Ser Uncertain significance ★★ ⚠ same type
ARSI p.Ala414Thr 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/arsi-p-arg543ser (accessed [today's date]).

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