Is FASN p.Ala487Thr (c.1459G>A) pathogenic?

FASN p.Ala487Thr (c.1459G>A) is classified Uncertain significance in FASN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-23). AlphaMissense: likely benign (0.0708); Ultra-rare (popmax 0.0202%, eas); Associated with Epileptic encephalopathy.

What condition is associated with FASN p.Ala487Thr (c.1459G>A)?

FASN p.Ala487Thr (c.1459G>A) is associated with Epileptic encephalopathy (ClinVar).

How common is FASN p.Ala487Thr (c.1459G>A) in the general population?

FASN p.Ala487Thr (c.1459G>A) is ultra-rare (popmax 0.0202%, eas) (gnomAD).

What do computational predictors say about FASN p.Ala487Thr (c.1459G>A)?

AlphaMissense predicts likely benign (score 0.0708) — an in-silico prediction, not a clinical call.

FASN p.Ala487Thr

c.1459G>A · rs372434423 · VCV1507994

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0708 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0202%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Epileptic encephalopathy

Computational evidence

Protein change
AlphaMissense	0.0708	likely benign
REVEL	0.007	strongly benign-leaning
SaProt	LLR -6.34	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 -11	GERP -3.3
Regional constraint	o/e 0.98	unconstrained · MANE · 973 bp · p 0.76 · regional, not allelic
Overall
CADD	0.067	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 0.0202% East Asian · 9/44,616 alleles

Filtering AF 0.0105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00783%

Overall 0.00456% 73/1,601,166 alleles · ultra-rare exomes 63/1,448,920 · genomes 10/152,246 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0202%	4,957
Remaining individualsnot grpmax-eligible	0.0161%	6,193
African / African-American	0.0107%	9,346
European (non-Finnish)	0.00358%	27,958
South Asian	0.00332%	30,089
Admixed American	0.00168%	59,492

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: FASN
Protein: p.Ala487Thr
Coding: c.1459G>A
MANE Select: NM_004104
dbSNP: rs372434423
Type: single nucleotide variant
Location: chr17:82091255 (GRCh38)
Gene constraint: LOEUF 0.284 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.65 · 34 PDB
Residue 487: the 'acyl and malonyl transferases' region

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

Disease context

Epileptic encephalopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FASN p.Ala487Ser Uncertain significance ★ ⚠ same residue
FASN c.3733-3C>T Uncertain significance ★★ same condition
FASN c.655+3G>T Uncertain significance ★★ same condition
FASN p.Ala1073Ser Uncertain significance ★★ ⚠ same condition
FASN p.Ala1272Val Uncertain significance ★★ ⚠ same condition
FASN p.Ala1285Val Uncertain significance ★★ ⚠ same condition
FASN p.Ala1569Ser Uncertain significance ★★ ⚠ same condition
FASN p.Ala1684Thr Uncertain significance ★★ same condition

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/fasn-p-ala487thr (accessed [today's date]).

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