Is HARS2 p.Ala38= (c.114A>G) pathogenic?

HARS2 p.Ala38= (c.114A>G) is classified Likely benign in HARS2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-12-11). Very rare (popmax 0.0022%, sas); Associated with HARS2-related disorder.

What condition is associated with HARS2 p.Ala38= (c.114A>G)?

HARS2 p.Ala38= (c.114A>G) is associated with HARS2-related disorder (ClinVar).

How common is HARS2 p.Ala38= (c.114A>G) in the general population?

HARS2 p.Ala38= (c.114A>G) is very rare (popmax 0.0022%, sas) (gnomAD).

HARS2 p.Ala38=

c.114A>G · rs2481363838 · VCV3031260

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

HARS2-related disorder

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 1.5	GERP 0.95, phastCons 1
Overall
CADD	9.44	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,086 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000136%

Overall 0.000124% 2/1,614,034 alleles · very rare exomes 2/1,461,730 · genomes 0/152,304 · joint denominator

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: HARS2
Protein: p.Ala38=
Coding: c.114A>G
MANE Select: NM_012208
dbSNP: rs2481363838
Type: single nucleotide variant
Location: chr5:140693596 (GRCh38)
Gene constraint: LOEUF 0.865 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.44

Full HARS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

HARS2-related disorder

Similar variants

HARS2 p.Tyr108Ter Pathogenic/Likely pathogenic ★★ same condition
HARS2 p.Arg138His Uncertain significance ★★ ⚠ same condition
HARS2 p.Cys380Ser Likely pathogenic ★ same condition
HARS2 p.Val368Met Likely pathogenic ★ same condition
HARS2 c.634-2A>G Conflicting classifications of pathogenicity ★ same condition
HARS2 p.Arg150Cys Conflicting classifications of pathogenicity ★ ⚠ same condition
HARS2 c.109-92G>A Likely benign same condition
HARS2 p.Cys24fs Conflicting classifications of pathogenicity ★ 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/hars2-p-ala38 (accessed [today's date]).

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