Is FA2H p.Ser268Phe (c.803C>T) pathogenic?

FA2H p.Ser268Phe (c.803C>T) is classified Likely benign in FA2H (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-22). AlphaMissense: ambiguous (0.3605); Very rare (popmax 0.00406%, afr); Associated with Spastic paraplegia.

What condition is associated with FA2H p.Ser268Phe (c.803C>T)?

FA2H p.Ser268Phe (c.803C>T) is associated with Spastic paraplegia (ClinVar).

How common is FA2H p.Ser268Phe (c.803C>T) in the general population?

FA2H p.Ser268Phe (c.803C>T) is very rare (popmax 0.00406%, afr) (gnomAD).

What do computational predictors say about FA2H p.Ser268Phe (c.803C>T)?

AlphaMissense predicts ambiguous (score 0.3605) — an in-silico prediction, not a clinical call.

FA2H p.Ser268Phe

c.803C>T · rs142644174 · VCV2191061

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3605 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00406%, afr)

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.3605	ambiguous
REVEL	0.521	indeterminate
SaProt	LLR -5.12	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 61 kb · p 0.86 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00406% African / African-American · 3/73,956 alleles

Filtering AF 0.00108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000499%

Overall 0.000318% 5/1,573,628 alleles · very rare exomes 4/1,421,624 · genomes 1/152,004 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00406%	24,652
European (non-Finnish)	0.000172%	580,211

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.Ser268Phe
Coding: c.803C>T
MANE Select: NM_024306
dbSNP: rs142644174
Type: single nucleotide variant
Location: chr16:74716583 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.53
Residue 268: 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 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
FA2H p.Gly258Ser 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-ser268phe (accessed [today's date]).

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