Is AMPH p.Gln21Pro (c.62A>C) pathogenic?

AMPH p.Gln21Pro (c.62A>C) is classified Uncertain significance in AMPH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely pathogenic (0.9957); Absent from gnomAD v4.1.

How common is AMPH p.Gln21Pro (c.62A>C) in the general population?

AMPH p.Gln21Pro (c.62A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AMPH p.Gln21Pro (c.62A>C)?

AlphaMissense predicts likely pathogenic (score 0.9957) — an in-silico prediction, not a clinical call.

AMPH p.Gln21Pro

c.62A>C · VCV4048014

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9957 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9957	likely pathogenic · top 8% in AMPH
REVEL	0.307	indeterminate
SaProt	LLR -10.38	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 166 kb · p 1e-06 · regional, not allelic
Overall
CADD	26.6	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: AMPH
Protein: p.Gln21Pro
Coding: c.62A>C
MANE Select: NM_001635
Type: single nucleotide variant
Location: chr7:38631290 (GRCh38)
Gene constraint: LOEUF 0.697 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.84 · 6 PDB
Residue 21: 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-gln21pro (accessed [today's date]).

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