Is EME1 p.Phe321Cys (c.962T>G) pathogenic?

EME1 p.Phe321Cys (c.962T>G) is classified Uncertain significance in EME1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-19). AlphaMissense: ambiguous (0.4462); Very rare (popmax 0.00267%, afr).

How common is EME1 p.Phe321Cys (c.962T>G) in the general population?

EME1 p.Phe321Cys (c.962T>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about EME1 p.Phe321Cys (c.962T>G)?

AlphaMissense predicts ambiguous (score 0.4462) — an in-silico prediction, not a clinical call.

EME1 p.Phe321Cys

c.962T>G · VCV3844612

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4462 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4462	ambiguous
REVEL	0.284	benign-leaning
SaProt	LLR -11.42	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 0.48, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 5,727 bp · p 0.068 · regional, not allelic
Overall
CADD	23.0	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 0.00267% African / African-American · 2/74,910 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,613,998 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,455
Admixed American	0.00167%	59,986

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: EME1
Protein: p.Phe321Cys
Coding: c.962T>G
MANE Select: NM_152463
Type: single nucleotide variant
Location: chr17:50378653 (GRCh38)
Gene constraint: LOEUF 1.248 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.81 · 14 PDB
Residue 321: the 'nuclease-like domain; forms the post-nick dna binding interface and is involved in dna recognition and bending' region; an α-helix

Full EME1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EME1 p.Ile282Thr Uncertain significance ★★ same type
EME1 p.Lys5Asn Benign ★★ same type
EME1 c.1113-24C>G Uncertain significance ★ same type
EME1 c.1113-33G>T Uncertain significance ★ same type
EME1 c.1113-34A>G Uncertain significance ★ same type
EME1 c.1113-8T>C Uncertain significance ★ same type
EME1 p.Ala235Val Uncertain significance ★ ⚠ same type
EME1 p.Ala24Gly 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/eme1-p-phe321cys (accessed [today's date]).

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