Is ATIC p.Thr116Ser (c.347C>G) pathogenic?

ATIC p.Thr116Ser (c.347C>G) is classified Benign in ATIC (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.085); Common (popmax 47.3%, sas) — too common for a highly-penetrant pathogenic allele; Associated with AICA-ribosiduria.

What condition is associated with ATIC p.Thr116Ser (c.347C>G)?

ATIC p.Thr116Ser (c.347C>G) is associated with AICA-ribosiduria (ClinVar).

How is AICA-ribosiduria inherited?

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

What do computational predictors say about ATIC p.Thr116Ser (c.347C>G)?

AlphaMissense predicts likely benign (score 0.085) — an in-silico prediction, not a clinical call.

ATIC p.Thr116Ser

Q: How common is ATIC p.Thr116Ser (c.347C>G) in the general population?

ATIC p.Thr116Ser (c.347C>G) is common (popmax 47.3%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.347C>G · rs2372536 · VCV801893

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.085 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 47.3%, sas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

AICA-ribosiduria

Computational evidence

Protein change
AlphaMissense	0.085	likely benign
REVEL	0.321	indeterminate
SaProt	LLR -6.66	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.4, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 38 kb · p 0.044 · regional, not allelic
Overall
CADD	23.5	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 47.3% South Asian · 43,053/90,992 alleles

Filtering AF 46.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 46.8%

Overall 31.9% 513,864/1,610,906 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	47.3%	2
Amishnot grpmax-eligible	41.5%	2
Ashkenazi Jewishnot grpmax-eligible	34.6%	3
Middle Eastern	33.4%	3
European (non-Finnish)	32.6%	3
Remaining individualsnot grpmax-eligible	32.5%	3
Admixed American	32.1%	3
Finnishnot grpmax-eligible	27.6%	4
East Asian	25.2%	4
African / African-American	8.55%	12

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: ATIC
Protein: p.Thr116Ser
Coding: c.347C>G
MANE Select: NM_004044
dbSNP: rs2372536
Type: single nucleotide variant
Location: chr2:215325297 (GRCh38)
Gene constraint: LOEUF 1.044 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.46 · 5 PDB
Residue 116: a UniProt-annotated variant site (in); the mgs-like domain; the 'imp cyclohydrolase' region

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

Disease context

AICA-ribosiduria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For AICA-ribosiduria (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Infancy, Neonatal

Similar variants

ATIC p.Ala183Glu Uncertain significance ★★ ⚠ same condition
ATIC p.His584Arg Uncertain significance ★★ ⚠ same condition
ATIC c.1098+60C>G Benign ★★ same condition
ATIC c.1228-30A>G Benign ★★ same condition
ATIC c.147-111A>T Benign ★★ same condition
ATIC c.1503+48A>T Benign ★★ same condition
ATIC c.380-18G>A Likely benign ★★ same condition
ATIC c.380-19A>C Benign ★★ 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/atic-p-thr116ser (accessed [today's date]).

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