Is HARS2 p.Ile477Phe (c.1429A>T) pathogenic?

HARS2 p.Ile477Phe (c.1429A>T) is classified Uncertain significance in HARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-12). AlphaMissense: likely benign (0.1367); Absent from gnomAD v4.1.

How common is HARS2 p.Ile477Phe (c.1429A>T) in the general population?

HARS2 p.Ile477Phe (c.1429A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HARS2 p.Ile477Phe (c.1429A>T)?

AlphaMissense predicts likely benign (score 0.1367) — an in-silico prediction, not a clinical call.

HARS2 p.Ile477Phe

c.1429A>T · rs775208983 · VCV1365393

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1367 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1367	likely benign
REVEL	0.563	indeterminate
SaProt	LLR -6.37	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.045	GERP -3
Overall
CADD	17.79	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HARS2
Protein: p.Ile477Phe
Coding: c.1429A>T
MANE Select: NM_012208
dbSNP: rs775208983
Type: single nucleotide variant
Location: chr5:140698046 (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

Similar variants

HARS2 p.Ile477Met Uncertain significance ★ ⚠ same residue
HARS2 c.633+1G>A Likely pathogenic ★★ same type
HARS2 p.Arg159Ter Pathogenic/Likely pathogenic ★★ same type
HARS2 p.Tyr108Ter Pathogenic/Likely pathogenic ★★ same type
HARS2 p.Arg129Cys Uncertain significance ★★ same type
HARS2 p.Arg129His Uncertain significance ★★ ⚠ same type
HARS2 p.Arg138His Uncertain significance ★★ ⚠ same type
HARS2 p.Arg168Cys Uncertain significance ★★ ⚠ same type

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-ile477phe (accessed [today's date]).

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