Is EHD2 p.Pro118Leu (c.353C>T) pathogenic?

EHD2 p.Pro118Leu (c.353C>T) is classified Uncertain significance in EHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-24). AlphaMissense: ambiguous (0.4182); Ultra-rare (popmax 0.0113%, nfe).

How common is EHD2 p.Pro118Leu (c.353C>T) in the general population?

EHD2 p.Pro118Leu (c.353C>T) is ultra-rare (popmax 0.0113%, nfe) (gnomAD).

What do computational predictors say about EHD2 p.Pro118Leu (c.353C>T)?

AlphaMissense predicts ambiguous (score 0.4182) — an in-silico prediction, not a clinical call.

EHD2 p.Pro118Leu

c.353C>T · VCV3843979

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4182 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0113%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4182	ambiguous
REVEL	0.697	pathogenic-leaning
SaProt	LLR -9.17	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 5.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 25 kb · p 0.00029 · regional, not allelic
Overall
CADD	25.0	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 0.0113% European (non-Finnish) · 133/1,179,956 alleles

Filtering AF 0.00969% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00905%

Overall 0.0091% 146/1,605,118 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0113%	8,872
Remaining individualsnot grpmax-eligible	0.0112%	8,920
African / African-American	0.004%	25,021
South Asian	0.0022%	45,542
Finnishnot grpmax-eligible	0.00181%	55,100

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: EHD2
Protein: p.Pro118Leu
Coding: c.353C>T
MANE Select: NM_014601
Type: single nucleotide variant
Location: chr19:47716965 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.15
Residue 118: the dynamin-type g domain

Full EHD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EHD2 p.Ala161Thr Uncertain significance ★ ⚠ same type
EHD2 p.Ala308Thr Uncertain significance ★ same type
EHD2 p.Ala340Glu Uncertain significance ★ ⚠ same type
EHD2 p.Ala365Val Uncertain significance ★ ⚠ same type
EHD2 p.Ala391Pro Uncertain significance ★ same type
EHD2 p.Ala413Thr Uncertain significance ★ ⚠ same type
EHD2 p.Ala442Asp Uncertain significance ★ ⚠ same type
EHD2 p.Ala461Val 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/ehd2-p-pro118leu (accessed [today's date]).

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