Is ATIC p.Pro471Ser (c.1411C>T) pathogenic?

ATIC p.Pro471Ser (c.1411C>T) is classified Benign in ATIC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.1846); Common (popmax 10.3%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about ATIC p.Pro471Ser (c.1411C>T)?

AlphaMissense predicts likely benign (score 0.1846) — an in-silico prediction, not a clinical call.

ATIC p.Pro471Ser

Q: How common is ATIC p.Pro471Ser (c.1411C>T) in the general population?

ATIC p.Pro471Ser (c.1411C>T) is common (popmax 10.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1411C>T · rs56117859 · VCV1650319

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1846 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 10.3%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1846	likely benign
REVEL	0.748	pathogenic-leaning
SaProt	LLR -10.55	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.8, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 38 kb · p 0.044 · regional, not allelic
Overall
CADD	25.5	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 10.3% African / African-American · 7,759/75,018 alleles

Filtering AF 10.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.1%

Overall 0.652% 10,517/1,614,134 alleles · common exomes 5,955/1,461,858 · genomes 4,562/152,276 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	10.3%	10
Remaining individualsnot grpmax-eligible	0.859%	116
Admixed American	0.858%	117
Middle Eastern	0.759%	132
European (non-Finnish)	0.136%	738
Finnishnot grpmax-eligible	0.0515%	1,940
South Asian	0.0285%	3,503
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602

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.Pro471Ser
Coding: c.1411C>T
MANE Select: NM_004044
dbSNP: rs56117859
Type: single nucleotide variant
Location: chr2:215346849 (GRCh38)
Gene constraint: LOEUF 1.044 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.46 · 5 PDB
Residue 471: 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-pro471ser (accessed [today's date]).

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