Is FA2H p.Phe265= (c.795C>T) pathogenic?

FA2H p.Phe265= (c.795C>T) is classified Uncertain significance in FA2H (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-13). Very rare (popmax 0.00238%, eas); Associated with Spastic paraplegia.

What condition is associated with FA2H p.Phe265= (c.795C>T)?

FA2H p.Phe265= (c.795C>T) is associated with Spastic paraplegia (ClinVar).

How common is FA2H p.Phe265= (c.795C>T) in the general population?

FA2H p.Phe265= (c.795C>T) is very rare (popmax 0.00238%, eas) (gnomAD).

FA2H p.Phe265=

c.795C>T · rs886043274 · VCV285971

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00238%, eas)

Conditions

Spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.25	acceptor gain · deltas
Constraint at this position
Conservation	phyloP -0.35	GERP -2.8, phastCons 0.006
Overall
CADD	15.16	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00238% East Asian · 1/41,996 alleles

Filtering AF 0.00148% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00126%

Overall 0.00192% 30/1,562,880 alleles · very rare exomes 29/1,410,870 · genomes 1/152,010 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00238%	41,996
European (non-Finnish)	0.00216%	46,206
Admixed American	0.00192%	52,190
Remaining individualsnot grpmax-eligible	0.00165%	60,678
African / African-American	0.00136%	73,620
South Asian	0.00117%	85,836

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.Phe265=
Coding: c.795C>T
MANE Select: NM_024306
dbSNP: rs886043274
Type: single nucleotide variant
Location: chr16:74716591 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.53
Residue 265: 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.Phe265Cys 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-phe265 (accessed [today's date]).

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