Is AMPH p.Arg457Gln (c.1370G>A) pathogenic?

AMPH p.Arg457Gln (c.1370G>A) is classified Likely benign in AMPH (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-26). AlphaMissense: likely benign (0.0603); Rare (popmax 0.611%, mid).

How common is AMPH p.Arg457Gln (c.1370G>A) in the general population?

AMPH p.Arg457Gln (c.1370G>A) is rare (popmax 0.611%, mid) (gnomAD).

What do computational predictors say about AMPH p.Arg457Gln (c.1370G>A)?

AlphaMissense predicts likely benign (score 0.0603) — an in-silico prediction, not a clinical call.

AMPH p.Arg457Gln

c.1370G>A · rs771596953 · VCV2314829

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0603 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.611%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0603	likely benign
REVEL	0.065	moderately benign-leaning
SaProt	LLR -5.28	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 -6.8	GERP -2.9
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.37 · regional, not allelic
Overall
CADD	0.147	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.611% Middle Eastern · 37/6,060 alleles

Filtering AF 0.455% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.402%

Overall 0.0142% 229/1,613,994 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.611%	164
Admixed American	0.045%	2,223
Remaining individualsnot grpmax-eligible	0.0384%	2,604
African / African-American	0.016%	6,251
European (non-Finnish)	0.0102%	9,833
East Asian	0.00669%	14,951
South Asian	0.00549%	18,215
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606

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: AMPH
Protein: p.Arg457Gln
Coding: c.1370G>A
MANE Select: NM_001635
dbSNP: rs771596953
Type: single nucleotide variant
Location: chr7:38417853 (GRCh38)
Gene constraint: LOEUF 0.697 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.84 · 6 PDB

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

Similar variants

AMPH p.Arg457Trp Uncertain significance ★ ⚠ same residue
AMPH c.1017+10T>C Likely benign ★★ same type
AMPH p.Thr586Met Likely benign ★★ same type
AMPH p.Ala10Thr Uncertain significance ★ ⚠ same type
AMPH p.Ala169Gly Uncertain significance ★ ⚠ same type
AMPH p.Ala239Ser Uncertain significance ★ ⚠ same type
AMPH p.Ala248Val Uncertain significance ★ ⚠ same type
AMPH p.Ala284Val 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/amph-p-arg457gln (accessed [today's date]).

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