Is LARS2 p.Pro712Ser (c.2134C>T) pathogenic?

LARS2 p.Pro712Ser (c.2134C>T) is classified Likely pathogenic in LARS2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-04-29). AlphaMissense: likely benign (0.1276); Very rare (popmax 0.000848%, nfe); Associated with hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome.

What condition is associated with LARS2 p.Pro712Ser (c.2134C>T)?

LARS2 p.Pro712Ser (c.2134C>T) is associated with hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome (ClinVar).

How common is LARS2 p.Pro712Ser (c.2134C>T) in the general population?

LARS2 p.Pro712Ser (c.2134C>T) is very rare (popmax 0.000848%, nfe) (gnomAD).

What do computational predictors say about LARS2 p.Pro712Ser (c.2134C>T)?

AlphaMissense predicts likely benign (score 0.1276) — an in-silico prediction, not a clinical call.

LARS2 p.Pro712Ser

c.2134C>T · rs764828665 · VCV1252055

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1276 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000848%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome

Computational evidence

Protein change
AlphaMissense	0.1276	likely benign ⚠ discordant with ClinVar
REVEL	0.091	moderately benign-leaning
SaProt	LLR -8.20	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.6, phastCons 0.99
Regional constraint	o/e 0.87	unconstrained · MANE · 153 kb · p 1.1e-05 · regional, not allelic
Overall
CADD	21.6	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 0.000848% European (non-Finnish) · 10/1,179,554 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.00062% 10/1,613,650 alleles · very rare exomes 9/1,461,346 · genomes 1/152,304 · 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: LARS2
Protein: p.Pro712Ser
Coding: c.2134C>T
MANE Select: NM_015340
dbSNP: rs764828665
Type: single nucleotide variant
Location: chr3:45517992 (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

hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome (Orphanet):

Onset: Neonatal

Similar variants

LARS2 p.Arg228His Likely pathogenic ★★ same condition
LARS2 p.Arg66Ter Pathogenic/Likely pathogenic ★★ same condition
LARS2 p.Asn153His Pathogenic/Likely pathogenic ★★ same condition
LARS2 p.Asp438Gly Likely pathogenic ★★ ⚠ same condition
LARS2 p.Gln147Pro Likely pathogenic ★★ ⚠ same condition
LARS2 p.Pro536Leu Likely pathogenic ★★ ⚠ same condition
LARS2 p.Arg605His Uncertain significance ★★ ⚠ same condition
LARS2 p.Asn847Ser 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/lars2-p-pro712ser (accessed [today's date]).

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