Is FA2H p.Pro264Ser (c.790C>T) pathogenic?

FA2H p.Pro264Ser (c.790C>T) is classified Uncertain significance in FA2H (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-22). AlphaMissense: likely pathogenic (0.8657); Very rare (popmax 0.00117%, sas); Associated with Spastic paraplegia.

What condition is associated with FA2H p.Pro264Ser (c.790C>T)?

FA2H p.Pro264Ser (c.790C>T) is associated with Spastic paraplegia (ClinVar).

How common is FA2H p.Pro264Ser (c.790C>T) in the general population?

FA2H p.Pro264Ser (c.790C>T) is very rare (popmax 0.00117%, sas) (gnomAD).

What do computational predictors say about FA2H p.Pro264Ser (c.790C>T)?

AlphaMissense predicts likely pathogenic (score 0.8657) — an in-silico prediction, not a clinical call.

FA2H p.Pro264Ser

c.790C>T · rs2544312575 · VCV2421319

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8657 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00117%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.8657	likely pathogenic
REVEL	0.803	moderately pathogenic-leaning
SaProt	LLR -14.23	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.29 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 0.36, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 61 kb · p 0.86 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00117% South Asian · 1/85,306 alleles

Overall 0.000128% 2/1,557,196 alleles · very rare exomes 2/1,405,044 · genomes 0/152,152 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00117%	85,306
European (non-Finnish)	8.68e-05%	1,152,258

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.Pro264Ser
Coding: c.790C>T
MANE Select: NM_024306
dbSNP: rs2544312575
Type: single nucleotide variant
Location: chr16:74716596 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.53
Residue 264: 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.Pro264Leu 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-pro264ser (accessed [today's date]).

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