Is EDEM1 p.Phe441Ser (c.1322T>C) pathogenic?

EDEM1 p.Phe441Ser (c.1322T>C) is classified Uncertain significance in EDEM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely pathogenic (0.5646); Ultra-rare (popmax 0.0413%, afr).

How common is EDEM1 p.Phe441Ser (c.1322T>C) in the general population?

EDEM1 p.Phe441Ser (c.1322T>C) is ultra-rare (popmax 0.0413%, afr) (gnomAD).

What do computational predictors say about EDEM1 p.Phe441Ser (c.1322T>C)?

AlphaMissense predicts likely pathogenic (score 0.5646) — an in-silico prediction, not a clinical call.

EDEM1 p.Phe441Ser

c.1322T>C · VCV4246579

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5646 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0413%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5646	likely pathogenic
REVEL	0.696	pathogenic-leaning
SaProt	LLR -9.04	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 28 kb · p 0.011 · regional, not allelic
Overall
CADD	25.4	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 0.0413% African / African-American · 31/75,036 alleles

Filtering AF 0.0298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.026%

Overall 0.00235% 38/1,614,094 alleles · ultra-rare exomes 17/1,461,830 · genomes 21/152,264 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0413%	2,421
Middle Eastern	0.0165%	6,062
South Asian	0.00329%	30,361
Remaining individualsnot grpmax-eligible	0.0032%	31,253
Admixed American	0.00167%	60,016

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: EDEM1
Protein: p.Phe441Ser
Coding: c.1322T>C
MANE Select: NM_014674
Type: single nucleotide variant
Location: chr3:5207257 (GRCh38)
Gene constraint: LOEUF 1.115 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.73

Full EDEM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EDEM1 p.Ala128Ser Uncertain significance ★ ⚠ same type
EDEM1 p.Ala134Val Uncertain significance ★ same type
EDEM1 p.Ala274Thr Uncertain significance ★ ⚠ same type
EDEM1 p.Ala304Val Uncertain significance ★ ⚠ same type
EDEM1 p.Ala409Ser Uncertain significance ★ ⚠ same type
EDEM1 p.Ala53Thr Uncertain significance ★ ⚠ same type
EDEM1 p.Ala5Ser Uncertain significance ★ ⚠ same type
EDEM1 p.Ala80Ser 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/edem1-p-phe441ser (accessed [today's date]).

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