Is FARS2 p.Arg338Ser (c.1012C>A) pathogenic?

FARS2 p.Arg338Ser (c.1012C>A) is classified Uncertain significance in FARS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-03). AlphaMissense: ambiguous (0.5549); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with FARS2 p.Arg338Ser (c.1012C>A)?

FARS2 p.Arg338Ser (c.1012C>A) is associated with Inborn genetic diseases, combined oxidative phosphorylation defect type 14 (ClinVar).

How common is FARS2 p.Arg338Ser (c.1012C>A) in the general population?

FARS2 p.Arg338Ser (c.1012C>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about FARS2 p.Arg338Ser (c.1012C>A)?

AlphaMissense predicts ambiguous (score 0.5549) — an in-silico prediction, not a clinical call.

FARS2 p.Arg338Ser

c.1012C>A · rs1167684566 · VCV940097

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5549 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5549	ambiguous
REVEL	0.363	indeterminate
SaProt	LLR -11.51	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 1.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 403 kb · p 0.021 · regional, not allelic
Overall
CADD	23.4	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 0.00267% African / African-American · 2/74,910 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000372% 6/1,613,930 alleles · very rare exomes 4/1,461,774 · genomes 2/152,156 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,455
European (non-Finnish)	0.000339%	294,985

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: FARS2
Protein: p.Arg338Ser
Coding: c.1012C>A
MANE Select: NM_006567
dbSNP: rs1167684566
Type: single nucleotide variant
Location: chr6:5545287 (GRCh38)
Gene constraint: LOEUF 1.015 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.17 · 9 PDB
Residue 338: an α-helix

Full FARS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: combined oxidative phosphorylation defect type 14

Similar variants

FARS2 p.Arg338Cys Uncertain significance ★★ ⚠ same residue
FARS2 p.Arg338= Benign/Likely benign ★★ same residue
FARS2 p.Arg338His Conflicting classifications of pathogenicity ★ ⚠ same residue
FARS2 p.Arg307Ter Pathogenic/Likely pathogenic ★★ same condition
FARS2 p.Arg386Ter Pathogenic/Likely pathogenic ★★ same condition
FARS2 p.Arg419Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
FARS2 p.Arg419His Pathogenic/Likely pathogenic ★★ same condition
FARS2 p.Gln100Ter 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/fars2-p-arg338ser (accessed [today's date]).

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