Is AMFR p.Leu477Arg (c.1430T>G) pathogenic?

AMFR p.Leu477Arg (c.1430T>G) is classified Uncertain significance in AMFR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-06). AlphaMissense: likely pathogenic (0.702); Very rare (popmax 0.00133%, afr).

How common is AMFR p.Leu477Arg (c.1430T>G) in the general population?

AMFR p.Leu477Arg (c.1430T>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about AMFR p.Leu477Arg (c.1430T>G)?

AlphaMissense predicts likely pathogenic (score 0.702) — an in-silico prediction, not a clinical call.

AMFR p.Leu477Arg

c.1430T>G · VCV4046682

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.702 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.702	likely pathogenic
REVEL	0.331	indeterminate
SaProt	LLR -10.16	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 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 23 kb · p 0.024 · regional, not allelic
Overall
CADD	27.4	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

Grpmax group 0.00133% African / African-American · 1/75,070 alleles

Overall 6.84e-05% 1/1,461,662 alleles · very rare

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: AMFR
Protein: p.Leu477Arg
Coding: c.1430T>G
MANE Select: NM_001144
Type: single nucleotide variant
Location: chr16:56369278 (GRCh38)
Gene constraint: LOEUF 0.633 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.30 · 13 PDB
Residue 477: a UniProt-annotated variant site (in spg89; pathogenic); a UniProt-annotated variant site (in spg89; likely pathogenic); an α-helix; the cue domain

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

Similar variants

AMFR p.Arg307Cys Uncertain significance ★★ ⚠ same type
AMFR p.Arg389His Uncertain significance ★★ ⚠ same type
AMFR c.707+1G>A Likely pathogenic ★ same type
AMFR p.Cys364Ter Pathogenic ★ same type
AMFR p.Ala231Ser Uncertain significance ★ ⚠ same type
AMFR p.Ala324Val Uncertain significance ★ ⚠ same type
AMFR p.Ala385Thr Uncertain significance ★ ⚠ same type
AMFR p.Ala407Pro 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/amfr-p-leu477arg (accessed [today's date]).

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