Is ANGPT4 p.Ser435= (c.1305A>C) pathogenic?

ANGPT4 p.Ser435= (c.1305A>C) is classified Benign in ANGPT4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-04-20). Low-frequency (popmax 4.03%, afr).

How common is ANGPT4 p.Ser435= (c.1305A>C) in the general population?

ANGPT4 p.Ser435= (c.1305A>C) is low-frequency (popmax 4.03%, afr) (gnomAD).

ANGPT4 p.Ser435=

c.1305A>C · rs62641668 · VCV771934

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.03%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.24	donor gain · deltas
Constraint at this position
Conservation	phyloP -3.5	GERP -4.4
Overall
CADD	0.432	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.03% African / African-American · 3,026/75,042 alleles

Filtering AF 3.91% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.86%

Overall 0.607% 9,806/1,614,190 alleles · low-frequency

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	6.87%	15
African / African-Americangrpmax	4.03%	25
Middle Eastern	2.39%	42
Remaining individualsnot grpmax-eligible	1.3%	77
Admixed American	0.993%	101
Finnishnot grpmax-eligible	0.985%	101
East Asian	0.316%	316
European (non-Finnish)	0.196%	511
South Asian	0.12%	836

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ANGPT4
Protein: p.Ser435=
Coding: c.1305A>C
MANE Select: NM_015985
dbSNP: rs62641668
Type: single nucleotide variant
Location: chr20:874330 (GRCh38)
Gene constraint: LOEUF 1.189 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.33
Residue 435: the fibrinogen c-terminal domain

Full ANGPT4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANGPT4 p.Glu117= Benign ★★ same type
ANGPT4 p.Ala233Ser Uncertain significance ★ ⚠ same type
ANGPT4 p.Ala275Thr Uncertain significance ★ ⚠ same type
ANGPT4 p.Ala277Val Uncertain significance ★ ⚠ same type
ANGPT4 p.Ala279Asp Uncertain significance ★ ⚠ same type
ANGPT4 p.Ala445Thr Uncertain significance ★ ⚠ same type
ANGPT4 p.Arg242His Uncertain significance ★ ⚠ same type
ANGPT4 p.Arg334Cys 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/angpt4-p-ser435 (accessed [today's date]).

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