Is ECD p.Phe212Leu (c.634T>C) pathogenic?

ECD p.Phe212Leu (c.634T>C) is classified Uncertain significance in ECD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-28). AlphaMissense: likely pathogenic (0.7655); Ultra-rare (popmax 0.0825%, mid).

How common is ECD p.Phe212Leu (c.634T>C) in the general population?

ECD p.Phe212Leu (c.634T>C) is ultra-rare (popmax 0.0825%, mid) (gnomAD).

What do computational predictors say about ECD p.Phe212Leu (c.634T>C)?

AlphaMissense predicts likely pathogenic (score 0.7655) — an in-silico prediction, not a clinical call.

ECD p.Phe212Leu

c.634T>C · VCV4246314

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7655 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0825%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7655	likely pathogenic · top 1% in ECD
REVEL	0.202	benign-leaning
SaProt	LLR -6.38	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	Δ0.39	acceptor loss, 10 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 9.1	GERP 1.7, phastCons 1
Overall
CADD	23.8	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 0.0825% Middle Eastern · 5/6,062 alleles

Filtering AF 0.0324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.021%

Overall 0.000479% 7/1,461,172 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0825%	1,212
European (non-Finnish)	0.00017%	589,925

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: ECD
Protein: p.Phe212Leu
Coding: c.634T>C
MANE Select: NM_006304 · reported on NM_007265
Type: single nucleotide variant
Location: chr10:73154405 (GRCh38)
Structure: AlphaFold pLDDT 69.87 · 140 PDB

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

Similar variants

ECD p.Phe212Cys Uncertain significance ★ ⚠ same residue
ECD p.Ala121Gly Uncertain significance ★ same type
ECD p.Ala122Ser Uncertain significance ★ ⚠ same type
ECD p.Ala150Thr Uncertain significance ★ ⚠ same type
ECD p.Ala234Ser Uncertain significance ★ ⚠ same type
ECD p.Ala329Val Uncertain significance ★ ⚠ same type
ECD p.Arg188Leu Uncertain significance ★ ⚠ same type
ECD p.Arg244Gln 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/ecd-p-phe212leu (accessed [today's date]).

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