Is ARG2 p.Thr154Pro (c.460A>C) pathogenic?

ARG2 p.Thr154Pro (c.460A>C) is classified Uncertain significance in ARG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-17). AlphaMissense: likely pathogenic (0.8166); Absent from gnomAD v4.1.

How common is ARG2 p.Thr154Pro (c.460A>C) in the general population?

ARG2 p.Thr154Pro (c.460A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ARG2 p.Thr154Pro (c.460A>C)?

AlphaMissense predicts likely pathogenic (score 0.8166) — an in-silico prediction, not a clinical call.

ARG2 p.Thr154Pro

c.460A>C · rs2503453598 · VCV3128441

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8166 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8166	likely pathogenic
REVEL	0.789	moderately pathogenic-leaning
SaProt	LLR -12.87	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.3	GERP 2.4, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 31 kb · p 0.02 · regional, not allelic
Overall
CADD	27.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ARG2
Protein: p.Thr154Pro
Coding: c.460A>C
MANE Select: NM_001172
dbSNP: rs2503453598
Type: single nucleotide variant
Location: chr14:67645740 (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-thr154pro (accessed [today's date]).

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