Is IARS2 p.Val331Ile (c.991G>A) pathogenic?

IARS2 p.Val331Ile (c.991G>A) is classified Conflicting classifications of pathogenicity in IARS2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-01-10). AlphaMissense: likely benign (0.0551); Ultra-rare (popmax 0.0253%, sas); Associated with cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome.

How common is IARS2 p.Val331Ile (c.991G>A) in the general population?

IARS2 p.Val331Ile (c.991G>A) is ultra-rare (popmax 0.0253%, sas) (gnomAD).

What do computational predictors say about IARS2 p.Val331Ile (c.991G>A)?

AlphaMissense predicts likely benign (score 0.0551) — an in-silico prediction, not a clinical call.

IARS2 p.Val331Ile

Q: What condition is associated with IARS2 p.Val331Ile (c.991G>A)?

IARS2 p.Val331Ile (c.991G>A) is associated with cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome (ClinVar).

Q: How is Cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.991G>A · rs201619737 · VCV1987468

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0551 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0253%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome

Computational evidence

Protein change
AlphaMissense	0.0551	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -6.74	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 -0.53	GERP -5.8
Regional constraint	o/e 0.90	unconstrained · MANE · 53 kb · p 0.00075 · regional, not allelic
Overall
CADD	0.158	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 0.0253% South Asian · 23/91,028 alleles

Filtering AF 0.0172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0146%

Overall 0.00211% 34/1,613,188 alleles · ultra-rare exomes 29/1,460,920 · genomes 5/152,268 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0253%	3,958
African / African-American	0.00267%	37,507
East Asian	0.00223%	44,866
Admixed American	0.00167%	60,014
Remaining individualsnot grpmax-eligible	0.0016%	62,424
European (non-Finnish)	0.000509%	196,551

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: IARS2
Protein: p.Val331Ile
Coding: c.991G>A
MANE Select: NM_018060
dbSNP: rs201619737
Type: single nucleotide variant
Location: chr1:220103487 (GRCh38)
Gene constraint: LOEUF 0.683 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.77

Full IARS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

IARS2 p.Arg817His Pathogenic/Likely pathogenic ★★ ⚠ same condition
IARS2 p.Ala12Thr Uncertain significance ★★ ⚠ same condition
IARS2 p.Ala701Val Uncertain significance ★★ same condition
IARS2 p.Ser339Phe Uncertain significance ★★ ⚠ same condition
IARS2 p.Thr388Met Uncertain significance ★★ ⚠ same condition
IARS2 p.Thr729Ile Uncertain significance ★★ same condition
IARS2 p.Gly874Arg Likely pathogenic ★ ⚠ same condition
IARS2 p.Trp297Ter Likely pathogenic ★ 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/iars2-p-val331ile (accessed [today's date]).

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