Is ATIC p.Ile228Phe (c.682A>T) pathogenic?

ATIC p.Ile228Phe (c.682A>T) is classified Likely benign in ATIC (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely benign (0.165); Rare (popmax 0.26%, sas).

How common is ATIC p.Ile228Phe (c.682A>T) in the general population?

ATIC p.Ile228Phe (c.682A>T) is rare (popmax 0.26%, sas) (gnomAD).

What do computational predictors say about ATIC p.Ile228Phe (c.682A>T)?

AlphaMissense predicts likely benign (score 0.165) — an in-silico prediction, not a clinical call.

ATIC p.Ile228Phe

c.682A>T · rs538280049 · VCV1049798

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.165 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.26%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.165	likely benign
REVEL	0.138	moderately benign-leaning
SaProt	LLR -5.16	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 -0.2	GERP -1.6
Regional constraint	o/e 1.07	unconstrained · MANE · 38 kb · p 0.044 · regional, not allelic
Overall
CADD	9.167	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 0.26% South Asian · 237/91,084 alleles

Filtering AF 0.233% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.222%

Overall 0.0156% 252/1,614,156 alleles · rare exomes 242/1,461,894 · genomes 10/152,262 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.26%	384
Remaining individualsnot grpmax-eligible	0.0208%	4,808
African / African-American	0.00267%	37,523

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.Ile228Phe
Coding: c.682A>T
MANE Select: NM_004044
dbSNP: rs538280049
Type: single nucleotide variant
Location: chr2:215326972 (GRCh38)
Gene constraint: LOEUF 1.044 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.46 · 5 PDB
Residue 228: the 'aicar formyltransferase' region; a β-strand

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

Similar variants

ATIC c.688+3A>G Uncertain significance ★★ same type
ATIC p.Ala140Thr Uncertain significance ★★ ⚠ same type
ATIC p.Ala183Glu Uncertain significance ★★ ⚠ same type
ATIC p.Ala510Thr Uncertain significance ★★ ⚠ same type
ATIC p.His584Arg Uncertain significance ★★ ⚠ same type
ATIC p.Ile491Val Uncertain significance ★★ ⚠ same type
ATIC p.Val154Ala Uncertain significance ★★ ⚠ same type
FN1 p.Ala2470Pro Uncertain significance ★★ ⚠ 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/atic-p-ile228phe (accessed [today's date]).

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