Is EHD1 p.Pro446Leu (c.1337C>T) pathogenic?

EHD1 p.Pro446Leu (c.1337C>T) is classified Uncertain significance in EHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-11). AlphaMissense: likely benign (0.2398); Ultra-rare (popmax 0.014%, nfe).

How common is EHD1 p.Pro446Leu (c.1337C>T) in the general population?

EHD1 p.Pro446Leu (c.1337C>T) is ultra-rare (popmax 0.014%, nfe) (gnomAD).

What do computational predictors say about EHD1 p.Pro446Leu (c.1337C>T)?

AlphaMissense predicts likely benign (score 0.2398) — an in-silico prediction, not a clinical call.

EHD1 p.Pro446Leu

c.1337C>T · rs201012032 · VCV2383326

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2398 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.014%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2398	likely benign
REVEL	0.374	indeterminate
SaProt	LLR -11.10	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 24 kb · p 2.1e-14 · regional, not allelic
Overall
CADD	24.8	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 0.014% European (non-Finnish) · 165/1,179,946 alleles

Filtering AF 0.0122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0116%

Overall 0.0126% 203/1,613,794 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0453%	2,207
European (non-Finnish)grpmax	0.014%	7,151
Remaining individualsnot grpmax-eligible	0.0128%	7,809
African / African-American	0.00134%	74,838

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: EHD1
Protein: p.Pro446Leu
Coding: c.1337C>T
MANE Select: NM_006795
dbSNP: rs201012032
Type: single nucleotide variant
Location: chr11:64854601 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI 0.11 (gnomAD)
Structure: AlphaFold pLDDT 89.65 · 5 PDB
Residue 446: the eh domain; an α-helix

Full EHD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EHD1 p.Ala273= Benign ★★ same type
EHD1 p.Gly464= Benign ★★ same type
EHD1 p.Leu114= Benign ★★ same type
EHD1 p.Leu187= Benign ★★ same type
EHD1 p.Ala304Gly Uncertain significance ★ ⚠ same type
EHD1 p.Ala308Thr Uncertain significance ★ ⚠ same type
EHD1 p.Ala373Val Uncertain significance ★ ⚠ same type
EHD1 p.Ala413Val 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/ehd1-p-pro446leu (accessed [today's date]).

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