Is ATIC p.Leu418Val (c.1252C>G) pathogenic?

ATIC p.Leu418Val (c.1252C>G) is classified Uncertain significance in ATIC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-07). AlphaMissense: ambiguous (0.3689); Very rare (popmax 0.000169%, nfe).

How common is ATIC p.Leu418Val (c.1252C>G) in the general population?

ATIC p.Leu418Val (c.1252C>G) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about ATIC p.Leu418Val (c.1252C>G)?

AlphaMissense predicts ambiguous (score 0.3689) — an in-silico prediction, not a clinical call.

ATIC p.Leu418Val

c.1252C>G · rs141731879 · VCV2407284

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3689 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3689	ambiguous
REVEL	0.721	pathogenic-leaning
SaProt	LLR -12.07	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense 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	24.9	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 0.000169% European (non-Finnish) · 2/1,180,000 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00132% 2/152,034 alleles · very rare

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.Leu418Val
Coding: c.1252C>G
MANE Select: NM_004044
dbSNP: rs141731879
Type: single nucleotide variant
Location: chr2:215344803 (GRCh38)
Gene constraint: LOEUF 1.044 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.46 · 5 PDB
Residue 418: the 'aicar formyltransferase' region; an α-helix

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

Similar variants

ATIC p.Leu418Phe Uncertain significance ★ ⚠ same residue
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

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-leu418val (accessed [today's date]).

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