Is ATIC p.Val154Ala (c.461T>C) pathogenic?

ATIC p.Val154Ala (c.461T>C) is classified Uncertain significance in ATIC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-12). AlphaMissense: likely pathogenic (0.6235); Ultra-rare (popmax 0.0933%, afr).

How common is ATIC p.Val154Ala (c.461T>C) in the general population?

ATIC p.Val154Ala (c.461T>C) is ultra-rare (popmax 0.0933%, afr) (gnomAD).

What do computational predictors say about ATIC p.Val154Ala (c.461T>C)?

AlphaMissense predicts likely pathogenic (score 0.6235) — an in-silico prediction, not a clinical call.

ATIC p.Val154Ala

c.461T>C · rs145011610 · VCV2701715

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6235 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0933%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6235	likely pathogenic
REVEL	0.602	indeterminate
SaProt	LLR -12.23	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 6.1	GERP 2.2, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 38 kb · p 0.044 · regional, not allelic
Overall
CADD	25.8	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 0.0933% African / African-American · 70/75,040 alleles

Filtering AF 0.0756% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0692%

Overall 0.0226% 365/1,614,146 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0933%	1,072
Admixed American	0.0267%	3,752
European (non-Finnish)	0.0225%	4,436
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.016%	6,251
South Asian	0.0022%	45,543

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.Val154Ala
Coding: c.461T>C
MANE Select: NM_004044
dbSNP: rs145011610
Type: single nucleotide variant
Location: chr2:215326068 (GRCh38)
Gene constraint: LOEUF 1.044 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.46 · 5 PDB
Residue 154: the 'imp cyclohydrolase' 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
FN1 p.Ala2470Pro Uncertain significance ★★ ⚠ same type
FN1 p.Arg2357Cys 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-val154ala (accessed [today's date]).

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