Is AMFR p.Ile449Val (c.1345A>G) pathogenic?

AMFR p.Ile449Val (c.1345A>G) is classified Uncertain significance in AMFR (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-29). AlphaMissense: likely benign (0.0912); Very rare (popmax 0.00446%, eas).

How common is AMFR p.Ile449Val (c.1345A>G) in the general population?

AMFR p.Ile449Val (c.1345A>G) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about AMFR p.Ile449Val (c.1345A>G)?

AlphaMissense predicts likely benign (score 0.0912) — an in-silico prediction, not a clinical call.

AMFR p.Ile449Val

c.1345A>G · rs761117811 · VCV2399009

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0912 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0912	likely benign
REVEL	0.122	moderately benign-leaning
SaProt	LLR -4.92	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 5.1	GERP 1.6, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 23 kb · p 0.024 · regional, not allelic
Overall
CADD	21.4	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 0.00446% East Asian · 2/44,880 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000496% 8/1,614,096 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,440
South Asian	0.00329%	30,357
European (non-Finnish)	0.000254%	393,338

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.Ile449Val
Coding: c.1345A>G
MANE Select: NM_001144
dbSNP: rs761117811
Type: single nucleotide variant
Location: chr16:56385954 (GRCh38)
Gene constraint: LOEUF 0.633 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.30 · 13 PDB
Residue 449: a UniProt-annotated variant site (in spg89; pathogenic); a UniProt-annotated variant site (in spg89; likely pathogenic)

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

Similar variants

AMFR p.Ile449Phe Uncertain significance ★ ⚠ same residue
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

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-ile449val (accessed [today's date]).

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