Is ABCA2 p.Ser1378Phe (c.4133C>T) pathogenic?

ABCA2 p.Ser1378Phe (c.4133C>T) is classified Uncertain significance in ABCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-08). AlphaMissense: likely benign (0.2045); Ultra-rare (popmax 0.0115%, nfe).

How common is ABCA2 p.Ser1378Phe (c.4133C>T) in the general population?

ABCA2 p.Ser1378Phe (c.4133C>T) is ultra-rare (popmax 0.0115%, nfe) (gnomAD).

What do computational predictors say about ABCA2 p.Ser1378Phe (c.4133C>T)?

AlphaMissense predicts likely benign (score 0.2045) — an in-silico prediction, not a clinical call.

ABCA2 p.Ser1378Phe

c.4133C>T · VCV3510071

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2045 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0115%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2045	likely benign
REVEL	0.464	indeterminate
SaProt	LLR -9.85	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.3, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,453 bp · p 0.54 · regional, not allelic
Overall
CADD	22.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S1377F vs ClinVar S1378F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0115% European (non-Finnish) · 136/1,179,452 alleles

Filtering AF 0.00995% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00932%

Overall 0.00875% 141/1,611,290 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0115%	8,672
Remaining individualsnot grpmax-eligible	0.00481%	20,795
Admixed American	0.00167%	59,876
African / African-American	0.00133%	74,920

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: ABCA2
Protein: p.Ser1378Phe
Coding: c.4133C>T
MANE Select: NM_001606
Type: single nucleotide variant
Location: chr9:137014275 (GRCh38)
Gene constraint: LOEUF 0.436 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.46
Residue 1378: a UniProt-annotated variant site (in idpogsa)

Full ABCA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCA2 p.Gln1370Ter Likely pathogenic ★★ same type
ABCA2 c.3883-3C>T Uncertain significance ★★ same type
ABCA2 p.Ala1357Thr Uncertain significance ★★ ⚠ same type
ABCA2 p.Ala1620Thr Uncertain significance ★★ ⚠ same type
ABCA2 p.Ala1645Val Uncertain significance ★★ ⚠ same type
ABCA2 p.Ala1715Ser Uncertain significance ★★ ⚠ same type
ABCA2 p.Ala2180Thr Uncertain significance ★★ ⚠ same type
ABCA2 p.Ala2206Val 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/abca2-p-ser1378phe (accessed [today's date]).

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