Is HARS1 p.Pro67Ser (c.199C>T) pathogenic?

HARS1 p.Pro67Ser (c.199C>T) is classified Uncertain significance in HARS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-11-26). AlphaMissense: ambiguous (0.4559); Very rare (popmax 0.0011%, sas); Associated with Usher syndrome type 3B.

What condition is associated with HARS1 p.Pro67Ser (c.199C>T)?

HARS1 p.Pro67Ser (c.199C>T) is associated with Usher syndrome type 3B (ClinVar).

How common is HARS1 p.Pro67Ser (c.199C>T) in the general population?

HARS1 p.Pro67Ser (c.199C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about HARS1 p.Pro67Ser (c.199C>T)?

AlphaMissense predicts ambiguous (score 0.4559) — an in-silico prediction, not a clinical call.

HARS1 p.Pro67Ser

c.199C>T · rs1581516557 · VCV651299

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4559 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Usher syndrome type 3B

Computational evidence

Protein change
AlphaMissense	0.4559	ambiguous
REVEL	0.635	indeterminate
SaProt	LLR -13.90	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 8,129 bp · p 0.28 · regional, not allelic
Overall
CADD	27.5	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 0.0011% South Asian · 1/91,068 alleles

Overall 6.84e-05% 1/1,461,554 alleles · very rare

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: HARS1
Protein: p.Pro67Ser
Coding: c.199C>T
MANE Select: NM_002109
dbSNP: rs1581516557
Type: single nucleotide variant
Location: chr5:140683201 (GRCh38)
Gene constraint: LOEUF 0.957 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.06 · 10 PDB
Residue 67: an α-helix

Full HARS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Usher syndrome type 3B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HARS1 p.Pro67Leu Uncertain significance ★★ ⚠ same residue
HARS1 c.1195-1G>A Uncertain significance ★★ same condition
HARS1 c.1311+4T>C Uncertain significance ★★ same condition
HARS1 c.1312-1G>A Uncertain significance ★★ same condition
HARS1 c.631-3C>A Uncertain significance ★★ same condition
HARS1 c.90+4A>C Uncertain significance ★★ same condition
HARS1 c.952-3C>A Uncertain significance ★★ same condition
HARS1 p.Ala2Thr 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/hars1-p-pro67ser (accessed [today's date]).

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