Is LARS2 p.Pro507Arg (c.1520C>G) pathogenic?

LARS2 p.Pro507Arg (c.1520C>G) is classified Conflicting classifications of pathogenicity in LARS2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-05-23). AlphaMissense: likely benign (0.2542); Very rare (popmax 0.000593%, nfe); Associated with Rare genetic deafness.

What condition is associated with LARS2 p.Pro507Arg (c.1520C>G)?

LARS2 p.Pro507Arg (c.1520C>G) is associated with Rare genetic deafness (ClinVar).

How common is LARS2 p.Pro507Arg (c.1520C>G) in the general population?

LARS2 p.Pro507Arg (c.1520C>G) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about LARS2 p.Pro507Arg (c.1520C>G)?

AlphaMissense predicts likely benign (score 0.2542) — an in-silico prediction, not a clinical call.

LARS2 p.Pro507Arg

c.1520C>G · rs1553635112 · VCV517248

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2542 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Rare genetic deafness

Computational evidence

Protein change
AlphaMissense	0.2542	likely benign
REVEL	0.748	pathogenic-leaning
SaProt	LLR -14.90	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 153 kb · p 1.1e-05 · regional, not allelic
Overall
CADD	26.1	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 0.000593% European (non-Finnish) · 7/1,179,550 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,613,098 alleles · very rare exomes 6/1,460,918 · genomes 1/152,180 · 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: LARS2
Protein: p.Pro507Arg
Coding: c.1520C>G
MANE Select: NM_015340
dbSNP: rs1553635112
Type: single nucleotide variant
Location: chr3:45491797 (GRCh38)
Gene constraint: LOEUF 0.808 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.57

Full LARS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Similar variants

LARS2 c.(?_2533 Likely pathogenic ★ same condition
LARS2 c.235-2A>G Likely pathogenic ★★ same type
LARS2 p.Arg228His Likely pathogenic ★★ same type
LARS2 p.Arg663Trp Pathogenic/Likely pathogenic ★★ same type
LARS2 p.Arg66Ter Pathogenic/Likely pathogenic ★★ same type
LARS2 p.Asn153His Pathogenic/Likely pathogenic ★★ same type
LARS2 p.Asp438Gly Likely pathogenic ★★ ⚠ same type
LARS2 p.Gln147Pro Likely pathogenic ★★ ⚠ 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/lars2-p-pro507arg (accessed [today's date]).

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