Is EPAS1 p.Ser12Leu (c.35C>T) pathogenic?

EPAS1 p.Ser12Leu (c.35C>T) is classified Likely benign in EPAS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-13). AlphaMissense: ambiguous (0.351); Ultra-rare (popmax 0.0517%, amr); Associated with Inborn genetic diseases.

What condition is associated with EPAS1 p.Ser12Leu (c.35C>T)?

EPAS1 p.Ser12Leu (c.35C>T) is associated with Inborn genetic diseases (ClinVar).

How common is EPAS1 p.Ser12Leu (c.35C>T) in the general population?

EPAS1 p.Ser12Leu (c.35C>T) is ultra-rare (popmax 0.0517%, amr) (gnomAD).

What do computational predictors say about EPAS1 p.Ser12Leu (c.35C>T)?

AlphaMissense predicts ambiguous (score 0.351) — an in-silico prediction, not a clinical call.

EPAS1 p.Ser12Leu

c.35C>T · rs376889179 · VCV2456384

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.351 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0517%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.351	ambiguous
REVEL	0.11	moderately benign-leaning
SaProt	LLR -8.46	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 78 kb · p 0.0012 · regional, not allelic
Overall
CADD	24.9	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 0.0517% Admixed American · 31/60,012 alleles

Filtering AF 0.0374% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0325%

Overall 0.00743% 120/1,614,030 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.159%	630
Admixed Americangrpmax	0.0517%	1,936
Remaining individualsnot grpmax-eligible	0.0176%	5,681
Middle Eastern	0.0164%	6,084
European (non-Finnish)	0.00229%	43,705
South Asian	0.0022%	45,543
African / African-American	0.00134%	74,902

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: EPAS1
Protein: p.Ser12Leu
Coding: c.35C>T
MANE Select: NM_001430
dbSNP: rs376889179
Type: single nucleotide variant
Location: chr2:46346881 (GRCh38)
Gene constraint: LOEUF 0.366 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.41 · 43 PDB
Residue 12: the 'disordered' region

Full EPAS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EPAS1 p.Ser12Trp Uncertain significance ★ ⚠ same residue
EPAS1 p.Ser12= Likely benign ★ same residue
EPAS1 p.Ala439Gly Uncertain significance ★★ ⚠ same condition
EPAS1 p.Ala463Thr Uncertain significance ★★ ⚠ same condition
EPAS1 p.Ala698Pro Uncertain significance ★★ ⚠ same condition
EPAS1 p.Ala758Thr Uncertain significance ★★ ⚠ same condition
EPAS1 p.Ala81Thr Uncertain significance ★★ ⚠ same condition
EPAS1 p.Ala83Asp Uncertain significance ★★ ⚠ 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/epas1-p-ser12leu (accessed [today's date]).

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