Is LARS2 p.Ser72Phe (c.215C>T) pathogenic?

LARS2 p.Ser72Phe (c.215C>T) is classified Conflicting classifications of pathogenicity in LARS2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-19). AlphaMissense: likely benign (0.0743); Rare (popmax 0.201%, sas).

How common is LARS2 p.Ser72Phe (c.215C>T) in the general population?

LARS2 p.Ser72Phe (c.215C>T) is rare (popmax 0.201%, sas) (gnomAD).

What do computational predictors say about LARS2 p.Ser72Phe (c.215C>T)?

AlphaMissense predicts likely benign (score 0.0743) — an in-silico prediction, not a clinical call.

LARS2 p.Ser72Phe

c.215C>T · rs532725261 · VCV2904833

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0743 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.201%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0743	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -8.83	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.55	GERP -0.83, phastCons 0.052
Regional constraint	o/e 0.87	unconstrained · MANE · 153 kb · p 1.1e-05 · regional, not allelic
Overall
CADD	15.68	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 0.201% South Asian · 183/91,050 alleles

Filtering AF 0.177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.168%

Overall 0.0123% 198/1,613,112 alleles · rare exomes 186/1,460,882 · genomes 12/152,230 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.201%	498
Remaining individualsnot grpmax-eligible	0.0176%	5,679
Middle Eastern	0.0165%	6,062
African / African-American	0.00267%	37,478
European (non-Finnish)	8.48e-05%	1,179,179

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.Ser72Phe
Coding: c.215C>T
MANE Select: NM_015340
dbSNP: rs532725261
Type: single nucleotide variant
Location: chr3:45394668 (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

Similar variants

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
LARS2 p.Gln186Ter Pathogenic/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-ser72phe (accessed [today's date]).

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