Is APC p.Ala1358= (c.4074G>A) pathogenic?

APC p.Ala1358= (c.4074G>A) is classified Benign/Likely benign in APC (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-04-13). Ultra-rare (popmax 0.0164%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with APC p.Ala1358= (c.4074G>A)?

APC p.Ala1358= (c.4074G>A) is associated with hereditary neoplastic syndrome, familial adenomatous polyposis 1 (ClinVar).

How common is APC p.Ala1358= (c.4074G>A) in the general population?

APC p.Ala1358= (c.4074G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

APC p.Ala1358=

c.4074G>A · rs149782464 · VCV220144

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.89	GERP -4.7, phastCons 1
Overall
CADD	8.502	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00136% 22/1,613,904 alleles · ultra-rare exomes 20/1,461,848 · genomes 2/152,056 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
East Asian	0.00668%	14,961
African / African-American	0.00401%	24,966
Remaining individualsnot grpmax-eligible	0.0032%	31,242
Admixed American	0.00167%	59,978
Finnishnot grpmax-eligible	0.00156%	63,976
European (non-Finnish)	0.000932%	107,274

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: APC
Protein: p.Ala1358=
Coding: c.4074G>A
MANE Select: NM_000038
dbSNP: rs149782464
Type: single nucleotide variant
Location: chr5:112839668 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1358: the 'disordered' region

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial adenomatous polyposis 1

Similar variants

APC p.Ala1358Ser Uncertain significance ★★ same residue
APC p.Ala1358Glu Uncertain significance ★ same residue
APC p.Ala1358Gly Uncertain significance ★ same residue
APC p.Ala1358Thr Conflicting classifications of pathogenicity ★ same residue
APC p.Ala1358Val Conflicting classifications of pathogenicity ★ same residue
APC c.1312+3A>C Likely pathogenic ★★★ same condition
APC c.1312+3A>G Pathogenic ★★★ same condition
APC c.1312+5G>A Likely pathogenic ★★★ same condition

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/apc-p-ala1358 (accessed [today's date]).

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