Is FA2H p.Val180= (c.540G>T) pathogenic?

FA2H p.Val180= (c.540G>T) is classified Conflicting classifications of pathogenicity in FA2H (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-03). Ultra-rare (popmax 0.0813%, afr); Associated with Spastic paraplegia.

What condition is associated with FA2H p.Val180= (c.540G>T)?

FA2H p.Val180= (c.540G>T) is associated with Spastic paraplegia, hereditary spastic paraplegia 35 (ClinVar).

How common is FA2H p.Val180= (c.540G>T) in the general population?

FA2H p.Val180= (c.540G>T) is ultra-rare (popmax 0.0813%, afr) (gnomAD).

FA2H p.Val180=

c.540G>T · rs150423523 · VCV320497

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0813%, afr)

Conditions

Spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.31	GERP -0.14, phastCons 0.98
Overall
CADD	6.985	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0813% African / African-American · 61/75,052 alleles

Filtering AF 0.0649% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.059%

Overall 0.00415% 67/1,614,012 alleles · ultra-rare exomes 29/1,461,698 · genomes 38/152,314 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0813%	1,230
Remaining individualsnot grpmax-eligible	0.0048%	20,836
Admixed American	0.00333%	30,013
European (non-Finnish)	8.47e-05%	1,179,948

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.Val180=
Coding: c.540G>T
MANE Select: NM_024306
dbSNP: rs150423523
Type: single nucleotide variant
Location: chr16:74726298 (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

Also linked: hereditary spastic paraplegia 35

Similar variants

FA2H c.363+2T>C Pathogenic/Likely pathogenic ★★ same condition
FA2H c.506+1G>C Pathogenic/Likely pathogenic ★★ same condition
FA2H c.786+1G>A Pathogenic/Likely pathogenic ★★ same condition
FA2H p.Arg127Ter Pathogenic/Likely pathogenic ★★ same condition
FA2H p.Arg189Ter Pathogenic ★★ same condition
FA2H p.Arg197Ter Pathogenic/Likely pathogenic ★★ same condition
FA2H p.Arg235His Pathogenic/Likely pathogenic ★★ same condition
FA2H p.Arg269His Pathogenic/Likely 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-val180 (accessed [today's date]).

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