Is FA2H p.Pro274fs (c.821_822del) pathogenic?

FA2H p.Pro274fs (c.821822del) is classified Pathogenic in FA2H (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-15). Very rare (popmax 0.00175%, amr); Associated with Spastic paraplegia.

What condition is associated with FA2H p.Pro274fs (c.821_822del)?

FA2H p.Pro274fs (c.821_822del) is associated with Spastic paraplegia (ClinVar).

How common is FA2H p.Pro274fs (c.821_822del) in the general population?

FA2H p.Pro274fs (c.821_822del) is very rare (popmax 0.00175%, amr) (gnomAD).

FA2H p.Pro274fs

c.821_822del · rs878855083 · VCV241466

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00175%, amr)

Conditions

Spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 7
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.55	GERP 0.35

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00175% Admixed American · 1/57,016 alleles

Overall 0.000125% 2/1,598,358 alleles · very rare exomes 2/1,446,280 · genomes 0/152,078 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00175%	57,016
Remaining individualsnot grpmax-eligible	0.00161%	61,924

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.Pro274fs
Coding: c.821_822del
MANE Select: NM_024306
dbSNP: rs878855083
Type: Deletion
Location: chr16:74716564 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.53
Residue 274: the fatty acid hydroxylase 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.Pro274Ala Uncertain significance ★★ ⚠ same residue
FA2H p.Arg53_Ile58del Pathogenic ★★ same condition
FA2H p.Gly298fs Pathogenic ★★ same condition
FA2H p.Thr314fs Pathogenic/Likely pathogenic ★★ same condition
FA2H p.Tyr170_Ser171delinsTer Pathogenic ★★ same condition
FA2H p.Pro274Thr Uncertain significance ★★ ⚠ same residue
FA2H p.Ala8fs Pathogenic ★ same condition
FA2H p.Gln56fs Pathogenic ★ 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-pro274fs (accessed [today's date]).

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