Is AMPH p.Ile545Val (c.1633A>G) pathogenic?

AMPH p.Ile545Val (c.1633A>G) is classified Uncertain significance in AMPH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely benign (0.2773); Ultra-rare (popmax 0.0118%, nfe).

How common is AMPH p.Ile545Val (c.1633A>G) in the general population?

AMPH p.Ile545Val (c.1633A>G) is ultra-rare (popmax 0.0118%, nfe) (gnomAD).

What do computational predictors say about AMPH p.Ile545Val (c.1633A>G)?

AlphaMissense predicts likely benign (score 0.2773) — an in-silico prediction, not a clinical call.

AMPH p.Ile545Val

c.1633A>G · VCV4047891

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2773 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0118%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2773	likely benign
REVEL	0.191	benign-leaning
SaProt	LLR -5.71	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	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.37 · regional, not allelic
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.0118% European (non-Finnish) · 139/1,179,974 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00956%

Overall 0.00902% 145/1,607,388 alleles · ultra-rare exomes 138/1,455,216 · genomes 7/152,172 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0118%	8,489
Remaining individualsnot grpmax-eligible	0.00642%	15,584
Admixed American	0.00167%	60,000
African / African-American	0.00134%	74,884

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.Ile545Val
Coding: c.1633A>G
MANE Select: NM_001635
Type: single nucleotide variant
Location: chr7:38391993 (GRCh38)
Gene constraint: LOEUF 0.697 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.84 · 6 PDB
Residue 545: 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-ile545val (accessed [today's date]).

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