Is ARG2 p.Ser2Tyr (c.5C>A) pathogenic?

ARG2 p.Ser2Tyr (c.5C>A) is classified Uncertain significance in ARG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-14). AlphaMissense: likely benign (0.105); Ultra-rare (popmax 0.0298%, afr).

How common is ARG2 p.Ser2Tyr (c.5C>A) in the general population?

ARG2 p.Ser2Tyr (c.5C>A) is ultra-rare (popmax 0.0298%, afr) (gnomAD).

What do computational predictors say about ARG2 p.Ser2Tyr (c.5C>A)?

AlphaMissense predicts likely benign (score 0.105) — an in-silico prediction, not a clinical call.

ARG2 p.Ser2Tyr

c.5C>A · rs371082332 · VCV2589445

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.105 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0298%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.105	likely benign
REVEL	0.16	moderately benign-leaning
SaProt	LLR -8.41	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 2.5	GERP 0.52, phastCons 0.99
Regional constraint	o/e 0.89	unconstrained · MANE · 31 kb · p 0.02 · regional, not allelic
Overall
CADD	21.3	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 0.0298% African / African-American · 22/73,914 alleles

Filtering AF 0.0201% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.017%

Overall 0.00188% 30/1,599,690 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0298%	3,360
Middle Eastern	0.0165%	6,044
Admixed American	0.00344%	29,064
Remaining individualsnot grpmax-eligible	0.00323%	30,946
Finnishnot grpmax-eligible	0.00315%	31,796
European (non-Finnish)	8.52e-05%	1,173,246

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: ARG2
Protein: p.Ser2Tyr
Coding: c.5C>A
MANE Select: NM_001172
dbSNP: rs371082332
Type: single nucleotide variant
Location: chr14:67619982 (GRCh38)
Gene constraint: LOEUF 0.78 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.55 · 18 PDB

Full ARG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARG2 p.Ala308= Benign/Likely benign ★★ same type
ARG2 p.Arg4Trp Likely benign ★★ ⚠ same type
ARG2 p.Gly36= Benign ★★ same type
ARG2 p.Ala106Pro Uncertain significance ★ ⚠ same type
ARG2 p.Ala123Thr Uncertain significance ★ ⚠ same type
ARG2 p.Ala191Ser Uncertain significance ★ ⚠ same type
ARG2 p.Ala31Asp Uncertain significance ★ ⚠ same type
ARG2 p.Arg105Ser 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/arg2-p-ser2tyr (accessed [today's date]).

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