Is ATIC p.Pro516Leu (c.1547C>T) pathogenic?

ATIC p.Pro516Leu (c.1547C>T) is classified Uncertain significance in ATIC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-25). AlphaMissense: likely pathogenic (0.5673); Very rare (popmax 0.00619%, nfe).

How common is ATIC p.Pro516Leu (c.1547C>T) in the general population?

ATIC p.Pro516Leu (c.1547C>T) is very rare (popmax 0.00619%, nfe) (gnomAD).

What do computational predictors say about ATIC p.Pro516Leu (c.1547C>T)?

AlphaMissense predicts likely pathogenic (score 0.5673) — an in-silico prediction, not a clinical call.

ATIC p.Pro516Leu

c.1547C>T · VCV3444302

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5673 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00619%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5673	likely pathogenic
REVEL	0.624	indeterminate
SaProt	LLR -14.12	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.7, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 38 kb · p 0.044 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00619% European (non-Finnish) · 73/1,179,984 alleles

Filtering AF 0.00503% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00462%

Overall 0.00506% 74/1,461,852 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00619%	16,164
Remaining individualsnot grpmax-eligible	0.0016%	62,512

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.Pro516Leu
Coding: c.1547C>T
MANE Select: NM_004044
Type: single nucleotide variant
Location: chr2:215349137 (GRCh38)
Gene constraint: LOEUF 1.044 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.46 · 5 PDB
Residue 516: 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
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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-pro516leu (accessed [today's date]).

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