Is AMPH p.Arg290Gln (c.869G>A) pathogenic?

AMPH p.Arg290Gln (c.869G>A) is classified Uncertain significance in AMPH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-05). AlphaMissense: ambiguous (0.3771); Ultra-rare (popmax 0.0135%, afr).

How common is AMPH p.Arg290Gln (c.869G>A) in the general population?

AMPH p.Arg290Gln (c.869G>A) is ultra-rare (popmax 0.0135%, afr) (gnomAD).

What do computational predictors say about AMPH p.Arg290Gln (c.869G>A)?

AlphaMissense predicts ambiguous (score 0.3771) — an in-silico prediction, not a clinical call.

AMPH p.Arg290Gln

c.869G>A · VCV4640303

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3771 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0135%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3771	ambiguous
REVEL	0.228	benign-leaning
SaProt	LLR -5.77	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.37 · regional, not allelic
Overall
CADD	27.9	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 0.0135% African / African-American · 10/74,190 alleles

Filtering AF 0.00729% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00555%

Overall 0.00139% 22/1,586,942 alleles · ultra-rare exomes 15/1,434,790 · genomes 7/152,152 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0135%	7,419
Remaining individualsnot grpmax-eligible	0.00327%	30,598
South Asian	0.00232%	43,067
European (non-Finnish)	0.000685%	145,887

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.Arg290Gln
Coding: c.869G>A
MANE Select: NM_001635
Type: single nucleotide variant
Location: chr7:38462994 (GRCh38)
Gene constraint: LOEUF 0.697 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.84 · 6 PDB
Residue 290: the 'disordered' region

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

Similar variants

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
AMPH p.Ala287Thr 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-arg290gln (accessed [today's date]).

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