Is IARS2 p.Ser339Phe (c.1016C>T) pathogenic?

IARS2 p.Ser339Phe (c.1016C>T) is classified Uncertain significance in IARS2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-04-13). AlphaMissense: likely benign (0.1185); Rare (popmax 0.11%, nfe); Associated with cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome.

How common is IARS2 p.Ser339Phe (c.1016C>T) in the general population?

IARS2 p.Ser339Phe (c.1016C>T) is rare (popmax 0.11%, nfe) (gnomAD).

What do computational predictors say about IARS2 p.Ser339Phe (c.1016C>T)?

AlphaMissense predicts likely benign (score 0.1185) — an in-silico prediction, not a clinical call.

IARS2 p.Ser339Phe

Q: What condition is associated with IARS2 p.Ser339Phe (c.1016C>T)?

IARS2 p.Ser339Phe (c.1016C>T) 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.1016C>T · rs139437119 · VCV1032019

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1185 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.11%, nfe)

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	0.1185	likely benign
REVEL	0.131	moderately benign-leaning
SaProt	LLR -9.29	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 1.7	GERP 2.1, phastCons 0.005
Regional constraint	o/e 0.90	unconstrained · MANE · 53 kb · p 0.00075 · regional, not allelic
Overall
CADD	19.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.11% European (non-Finnish) · 1,299/1,179,564 alleles

Filtering AF 0.105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.103%

Overall 0.0858% 1,384/1,613,554 alleles · rare exomes 1,295/1,461,236 · genomes 89/152,318 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.11%	908
Remaining individualsnot grpmax-eligible	0.0897%	1,115
Admixed American	0.0217%	4,617
African / African-American	0.0187%	5,361
Middle Eastern	0.0165%	6,062
Finnishnot grpmax-eligible	0.00156%	63,994

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.Ser339Phe
Coding: c.1016C>T
MANE Select: NM_018060
dbSNP: rs139437119
Type: single nucleotide variant
Location: chr1:220103512 (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.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
IARS2 p.Ala341Val 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/iars2-p-ser339phe (accessed [today's date]).

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