Is FA2H p.Ala4Ser (c.10G>T) pathogenic?

FA2H p.Ala4Ser (c.10G>T) is classified Conflicting classifications of pathogenicity in FA2H (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-06). AlphaMissense: likely benign (0.1096); Ultra-rare (popmax 0.0221%, eas); Associated with Spastic paraplegia.

What condition is associated with FA2H p.Ala4Ser (c.10G>T)?

FA2H p.Ala4Ser (c.10G>T) is associated with Spastic paraplegia (ClinVar).

How common is FA2H p.Ala4Ser (c.10G>T) in the general population?

FA2H p.Ala4Ser (c.10G>T) is ultra-rare (popmax 0.0221%, eas) (gnomAD).

What do computational predictors say about FA2H p.Ala4Ser (c.10G>T)?

AlphaMissense predicts likely benign (score 0.1096) — an in-silico prediction, not a clinical call.

FA2H p.Ala4Ser

c.10G>T · rs1272032670 · VCV2175300

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1096 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0221%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.1096	likely benign
REVEL	0.163	moderately benign-leaning
SaProt	LLR -7.19	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 0.42, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 61 kb · p 0.86 · regional, not allelic
Overall
CADD	21.2	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 0.0221% East Asian · 7/31,662 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00727%

Overall 0.00061% 8/1,310,550 alleles · ultra-rare exomes 4/1,158,572 · genomes 4/151,978 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0221%	4,523
South Asian	0.00235%	42,562

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.Ala4Ser
Coding: c.10G>T
MANE Select: NM_024306
dbSNP: rs1272032670
Type: single nucleotide variant
Location: chr16:74774746 (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 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-ala4ser (accessed [today's date]).

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