Is FAAH2 p.Ala458Ser (c.1372G>T) pathogenic?

FAAH2 p.Ala458Ser (c.1372G>T) is classified Uncertain significance in FAAH2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2016-03-01). AlphaMissense: likely benign (0.3268); Ultra-rare (popmax 0.0292%, nfe).

How common is FAAH2 p.Ala458Ser (c.1372G>T) in the general population?

FAAH2 p.Ala458Ser (c.1372G>T) is ultra-rare (popmax 0.0292%, nfe) (gnomAD).

What do computational predictors say about FAAH2 p.Ala458Ser (c.1372G>T)?

AlphaMissense predicts likely benign (score 0.3268) — an in-silico prediction, not a clinical call.

FAAH2 p.Ala458Ser

c.1372G>T · rs147173444 · VCV223099

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3268 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0292%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.3268	likely benign
REVEL	0.509	indeterminate
SaProt	LLR -11.28	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4	GERP 0.7, phastCons 1
Regional constraint	o/e 1.73	unconstrained · MANE · 202 kb · p 2.2e-48 · regional, not allelic
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0292% European (non-Finnish) · 261/894,982 alleles

Filtering AF 0.0262% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0251%

Overall 0.0271% 328/1,209,408 alleles · ultra-rare exomes 312/1,097,697 · genomes 16/111,711 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0494%	2,026
Remaining individualsnot grpmax-eligible	0.0441%	2,267
European (non-Finnish)grpmax	0.0292%	3,429
Admixed American	0.0219%	4,566
South Asian	0.0159%	6,298
East Asian	0.0089%	11,230
African / African-American	0.00175%	57,138

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: FAAH2
Protein: p.Ala458Ser
Coding: c.1372G>T
MANE Select: NM_174912
dbSNP: rs147173444
Type: single nucleotide variant
Location: chrX:57448667 (GRCh38)
Structure: AlphaFold pLDDT 94.08

Full FAAH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FAAH2 c.1229-14A>T Benign ★★ same type
FAAH2 p.Arg274= Benign ★★ same type
FAAH2 p.Arg42Trp Benign ★★ same type
FAAH2 p.Pro468= Benign ★★ same type
FAAH2 c.742+5T>A Uncertain significance ★ same type
FAAH2 p.Ala115Val Uncertain significance ★ ⚠ same type
FAAH2 p.Ala157Asp Uncertain significance ★ ⚠ same type
FAAH2 p.Ala161Thr 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/faah2-p-ala458ser (accessed [today's date]).

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