Is ATIC p.Glu412Lys (c.1234G>A) pathogenic?

ATIC p.Glu412Lys (c.1234G>A) is classified Benign/Likely benign in ATIC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-27). AlphaMissense: likely benign (0.093); Low-frequency (popmax 1.12%, afr).

How common is ATIC p.Glu412Lys (c.1234G>A) in the general population?

ATIC p.Glu412Lys (c.1234G>A) is low-frequency (popmax 1.12%, afr) (gnomAD).

What do computational predictors say about ATIC p.Glu412Lys (c.1234G>A)?

AlphaMissense predicts likely benign (score 0.093) — an in-silico prediction, not a clinical call.

ATIC p.Glu412Lys

c.1234G>A · rs141872658 · VCV376861

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.093 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.12%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.093	likely benign
REVEL	0.501	indeterminate
SaProt	LLR -11.28	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 2.4, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 38 kb · p 0.044 · regional, not allelic
Overall
CADD	22.5	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 1.12% African / African-American · 843/75,030 alleles

Filtering AF 1.06% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.04%

Overall 0.0591% 954/1,613,988 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.12%	89
Admixed American	0.08%	1,250
Remaining individualsnot grpmax-eligible	0.0672%	1,488
Middle Eastern	0.0495%	2,021
East Asian	0.00223%	44,880
South Asian	0.0022%	45,525
European (non-Finnish)	0.00127%	78,664

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.Glu412Lys
Coding: c.1234G>A
MANE Select: NM_004044
dbSNP: rs141872658
Type: single nucleotide variant
Location: chr2:215344785 (GRCh38)
Gene constraint: LOEUF 1.044 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.46 · 5 PDB
Residue 412: the 'aicar formyltransferase' region; an α-helix

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-glu412lys (accessed [today's date]).

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