Is ECD p.Arg357Trp (c.1069C>T) pathogenic?

ECD p.Arg357Trp (c.1069C>T) is classified Uncertain significance in ECD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-17). AlphaMissense: likely benign (0.1006); Ultra-rare (popmax 0.0165%, mid).

How common is ECD p.Arg357Trp (c.1069C>T) in the general population?

ECD p.Arg357Trp (c.1069C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ECD p.Arg357Trp (c.1069C>T)?

AlphaMissense predicts likely benign (score 0.1006) — an in-silico prediction, not a clinical call.

ECD p.Arg357Trp

c.1069C>T · VCV3843266

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1006 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1006	likely benign
REVEL	0.116	moderately benign-leaning
SaProt	LLR -10.56	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP 2.2, phastCons 1
Overall
CADD	31.0	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 0.0165% Middle Eastern · 1/6,068 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00137% 22/1,608,382 alleles · ultra-rare exomes 21/1,457,260 · genomes 1/151,122 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,068
Admixed American	0.00669%	14,952
East Asian	0.00446%	22,415
Ashkenazi Jewishnot grpmax-eligible	0.0034%	29,448
Finnishnot grpmax-eligible	0.00316%	31,628
African / African-American	0.00269%	37,228
Remaining individualsnot grpmax-eligible	0.00161%	62,200
European (non-Finnish)	0.000765%	130,762

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.Arg357Trp
Coding: c.1069C>T
MANE Select: NM_007265
Type: single nucleotide variant
Location: chr10:73146334 (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.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
ECD p.Arg281Gln 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-arg357trp (accessed [today's date]).

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