Is AMPH p.Arg61Gln (c.182G>A) pathogenic?

AMPH p.Arg61Gln (c.182G>A) is classified Uncertain significance in AMPH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-20). AlphaMissense: likely pathogenic (0.8895); Ultra-rare (popmax 0.0164%, mid).

How common is AMPH p.Arg61Gln (c.182G>A) in the general population?

AMPH p.Arg61Gln (c.182G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about AMPH p.Arg61Gln (c.182G>A)?

AlphaMissense predicts likely pathogenic (score 0.8895) — an in-silico prediction, not a clinical call.

AMPH p.Arg61Gln

c.182G>A · VCV4047976

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8895 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8895	likely pathogenic
REVEL	0.284	benign-leaning
SaProt	LLR -12.80	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.50 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 166 kb · p 1e-06 · regional, not allelic
Overall
CADD	29.4	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 0.0164% Middle Eastern · 1/6,080 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00124% 20/1,613,898 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,080
European (non-Finnish)	0.00153%	65,554
South Asian	0.0011%	91,068

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.Arg61Gln
Coding: c.182G>A
MANE Select: NM_001635
Type: single nucleotide variant
Location: chr7:38503673 (GRCh38)
Gene constraint: LOEUF 0.697 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.84 · 6 PDB
Residue 61: the bar domain; an α-helix

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-arg61gln (accessed [today's date]).

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