Is FA2H p.Gln89Ter (c.265C>T) pathogenic?

FA2H p.Gln89Ter (c.265C>T) is classified Pathogenic in FA2H (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-25). Very rare (popmax 0.000176%, nfe); Associated with Spastic paraplegia.

What condition is associated with FA2H p.Gln89Ter (c.265C>T)?

FA2H p.Gln89Ter (c.265C>T) is associated with Spastic paraplegia (ClinVar).

How common is FA2H p.Gln89Ter (c.265C>T) in the general population?

FA2H p.Gln89Ter (c.265C>T) is very rare (popmax 0.000176%, nfe) (gnomAD).

FA2H p.Gln89Ter

c.265C>T · rs2544384008 · VCV2137845

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000176%, nfe)

Conditions

Spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 7
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP 0.18, phastCons 1
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000176% European (non-Finnish) · 2/1,138,430 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000132% 2/1,515,970 alleles · very rare exomes 2/1,363,666 · genomes 0/152,304 · joint denominator

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.Gln89Ter
Coding: c.265C>T
MANE Select: NM_024306
dbSNP: rs2544384008
Type: single nucleotide variant
Location: chr16:74774491 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.53

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.Gln89Leu 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
FA2H p.Glu365Gln 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-gln89ter (accessed [today's date]).

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