Is FA2H p.Glu15= (c.45G>A) pathogenic?

FA2H p.Glu15= (c.45G>A) is classified Likely benign in FA2H (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-15). Very rare (popmax 0.0038%, amr); Associated with Spastic paraplegia.

What condition is associated with FA2H p.Glu15= (c.45G>A)?

FA2H p.Glu15= (c.45G>A) is associated with Spastic paraplegia (ClinVar).

How common is FA2H p.Glu15= (c.45G>A) in the general population?

FA2H p.Glu15= (c.45G>A) is very rare (popmax 0.0038%, amr) (gnomAD).

FA2H p.Glu15=

c.45G>A · rs1038553022 · VCV2698790

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0038%, amr)

Conditions

Spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.57	GERP -1.9, phastCons 0.035
Overall
CADD	13.04	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0038% Admixed American · 1/26,310 alleles

Overall 0.000222% 3/1,352,912 alleles · very rare exomes 1/1,200,896 · genomes 2/152,016 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0039%	25,644
Admixed Americangrpmax	0.0038%	26,310

Remaining individuals 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: FA2H
Protein: p.Glu15=
Coding: c.45G>A
MANE Select: NM_024306
dbSNP: rs1038553022
Type: single nucleotide variant
Location: chr16:74774711 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.53
Residue 15: the cytochrome b5 heme-binding domain

Full FA2H gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Spastic paraplegia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FA2H p.Glu15Lys Uncertain significance ★ ⚠ same residue
FAAH p.Gly15Val Uncertain significance ★ ⚠ same residue
FA2H c.506+1G>C Pathogenic/Likely pathogenic ★★ same condition
FA2H p.Arg269His Pathogenic/Likely pathogenic ★★ same condition
FA2H p.Met1Val Pathogenic ★★ same condition
FA2H p.Pro44Gln Pathogenic/Likely pathogenic ★★ same condition
FA2H p.Pro44Ser Pathogenic/Likely pathogenic ★★ same condition
FA2H p.Arg269Cys 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/fa2h-p-glu15 (accessed [today's date]).

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