Is ATIC p.Pro260Leu (c.779C>T) pathogenic?

ATIC p.Pro260Leu (c.779C>T) is classified Uncertain significance in ATIC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: ambiguous (0.4155); Very rare (popmax 0.00686%, nfe).

How common is ATIC p.Pro260Leu (c.779C>T) in the general population?

ATIC p.Pro260Leu (c.779C>T) is very rare (popmax 0.00686%, nfe) (gnomAD).

What do computational predictors say about ATIC p.Pro260Leu (c.779C>T)?

AlphaMissense predicts ambiguous (score 0.4155) — an in-silico prediction, not a clinical call.

ATIC p.Pro260Leu

c.779C>T · rs750765780 · VCV2460623

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4155 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00686%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4155	ambiguous
REVEL	0.613	indeterminate
SaProt	LLR -13.81	damaging
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	29.4	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 0.00686% European (non-Finnish) · 81/1,180,034 alleles

Filtering AF 0.00563% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.00514% 83/1,613,964 alleles · very rare exomes 79/1,461,878 · genomes 4/152,086 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00686%	14,568
Remaining individualsnot grpmax-eligible	0.0016%	62,486
African / African-American	0.00134%	74,870

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.Pro260Leu
Coding: c.779C>T
MANE Select: NM_004044
dbSNP: rs750765780
Type: single nucleotide variant
Location: chr2:215332472 (GRCh38)
Gene constraint: LOEUF 1.044 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.46 · 5 PDB
Residue 260: the 'aicar formyltransferase' region

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-pro260leu (accessed [today's date]).

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